KR20220079883A - Novel substituted quinoline-8-hydrogen derivatives having androgen receptor degrading activity and uses thereof - Google Patents

Abstract

The present disclosure relates to novel compounds, pharmaceutical compositions containing such compounds, and their use in the prevention and treatment of cancer and related diseases and conditions. In some embodiments, the compounds disclosed herein exhibit androgen receptor degrading activity.

Description

Novel substituted quinoline-8-hydrogen derivatives having androgen receptor degrading activity and uses thereof

CROSS-REFERENCE TO RELATED APPLICATIONS

[1] This application claims priority to U.S. Provisional Patent Application No. 62/904,007, filed on September 23, 2019, which is incorporated herein by reference in its entirety.

Fields of the present disclosure

[2] The present disclosure relates to novel compounds, pharmaceutical compositions containing such compounds, and their use in the prevention and treatment of diseases and conditions, such as cancer. The compounds disclosed herein exhibit androgen receptor degrading activity.

[3] Androgens bind to the androgen receptor (AR) and regulate a wide range of physiological processes. For example, androgens are central to the AR signaling pathway and are therefore required for normal prostate development and function. Unfortunately, the AR signaling pathway is also implicated in the development and survival of cancers such as prostate cancer, breast cancer and other cancers (e.g., "Androgen Receptor in Prostate Cancer", Endocrine Reviews, 2004, 25(2)). , 276-308; and "Androgen receptors beyond prostate cancer: ann old marker as a new target", see Oncotarget, 2014, 6(2), 592-603).

[4] Traditional methods of treating AR-related cancers, such as prostate cancer, involve suppression of AR signaling through, for example, androgen deprivation therapy. Such treatment includes chemical and/or surgical castration. Alternatively, anti-androgen therapy may be pursued, whereby the patient is treated with an AR inhibitor such as Enzalutamide (XTANDI®). Although these treatment modalities have improved the prognosis for individuals with androgen receptor positive cancer, cancer progression is eventually observed and occurs, for example, through AR gene amplification and/or development of AR mutations.

[5] Therefore, there is a need to treat AR-positive cancers that arrest cancer progression even when an individual has experienced one or more previous therapies. One approach to achieve this goal is to exploit naturally occurring cellular ubiquitin-mediated degradation. Without wishing to be bound by any theory, it is believed that AR degradation may occur when both AR and ubiquitin ligase are bound and brought into proximity.

[6] Cereblon (“CRBN”) E3 ubiquitin ligase is a ubiquitin ligase that forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 and Cullin 4 . It functions as a substrate receptor by bringing the substrate into proximity for ubiquitination and subsequent degradation by the proteasome. Recently, it has been discovered that small molecule drugs, such as thalidomide and its close analogues lenalidomide and pomalidomide, can interact with CRBN and some other proteins simultaneously. . In doing so, CRBN can be used to degrade target proteins such as IKZF1 and IKZF3. This is thought to explain the anti-myeloma effect of thalidomide and related compounds.

[7] Accordingly, disclosed herein are compounds useful for the treatment of cancers such as prostate cancer. In some cases, the cancer is AR positive. The compounds disclosed herein are bifunctional molecules wherein one moiety of the molecule is capable of interacting with CRBN and the other moiety linked to the CRBN-interacting moiety of the molecule via a linking moiety is capable of interacting with AR.

Summary of the present disclosure

[8] In some embodiments, the present disclosure relates to a compound of Formula (1), or a pharmaceutically acceptable salt thereof:

In the above formula:

X ₁ is CR ₁ or N;

X ₂ is CR ₂ or N;

X ₃ is CR ₃ or N;

X ₄ is CR ₄ or N;

each of R ₁ , R ₂ , R ₃ , and R ₄ is independently selected from hydrogen, halogen, C ₁ -C ₃ alkoxy, and C ₁ -C ₃ haloalkyl, each of which is 0, 1, 2, or 3 substituted with R _S ;

each R ₅ is independently selected from halogen, hydroxyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl, —N(R ₉ ) ₂ , and —CN, which are each is substituted with 0, 1, 2, or 3 R _S ;

each R ₆ is independently selected from hydrogen, halogen, C ₁ -C ₃ alkyl, and C ₁ -C ₃ haloalkyl, each of which is substituted with 0, 1, 2, or 3 R _S ; two R ₆ groups taken together form oxo;

each R ₇ is independently selected from halogen, hydroxyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl, —N(R ₉ ) ₂ , and —CN, which are each is substituted with 0, 1, 2, or 3 R _S ;

each R ₈ is independently selected from hydrogen, hydroxyl, C ₁ -C ₃ alkyl, and C ₁ -C ₃ haloalkyl, each of which is substituted with 0, 1, 2, or 3 R _S ; two R ₈ groups taken together form oxo;

each R ₉ is independently hydrogen, C ₁ -C ₃ alkyl, -C(=O)-(C ₁ -C ₃ alkyl), -C(=O)-O-(C ₁ -C ₃ alkyl), and -C(=O)-NH-(C ₁ -C ₃ alkyl), each of which is substituted with 0, 1, 2, or 3 R _S ; two R ₉ groups taken together form a 3-6 membered heterocycle or heteroaryl;

each R _s is independently selected from halogen, hydroxyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl, —N(R ₉ ) ₂ , and —CN,

L is a linker of 1 to 16 carbon atoms in length, wherein at least one carbon atom is C(O), O, N(R ₉ ), S, C ₂ -alkenyl, C ₂ -alkynyl, cycloalkyl, aryl , heterocycle, or heteroaryl, wherein R ₉ , C ₂ -alkenyl, cycloalkyl, aryl, heterocycle, and heteroaryl are each independently substituted with 0, 1, 2, or 3 R _S become;

m is 0, 1, or 2;

n is 0, 1, 2, or 3;

o is 0, 1, 2, or 3;

wherein each hydrogen atom is independently and optionally replaced by a deuterium atom.

[9] In some embodiments, the compound of formula (1) can be a compound of formula (1A):

기는

[10] In some embodiments,

creeper

can be selected from

기는

[11] In some embodiments,

creeper

can be selected from

기는

[12] In some embodiments,

creeper

can be selected from

[13] In some embodiments, L is

can be selected from

[14] Also, as a method of treating cancer in a subject in need thereof, a compound of Formula (1) (eg, Formula (1A)), or a pharmaceutically acceptable salt thereof, or Formula ( Disclosed herein is a method comprising administering to the subject a pharmaceutical composition comprising the compound of 1) or a pharmaceutically acceptable salt thereof. In at least one embodiment, the pharmaceutical composition of the present disclosure may be for use in the treatment of (or in the manufacture of a medicament for) cancer in a subject in need thereof.

[15] In at least one embodiment, a therapeutically effective amount of a pharmaceutical composition of the present disclosure may be administered to a subject diagnosed with cancer. In some embodiments, the cancer is prostate cancer, head and neck cancer, skin cancer, sarcoma, renal cell carcinoma, adrenocortical carcinoma, bladder cancer, lung cancer, gastric carcinoma, esophageal carcinoma, pancreatic adenocarcinoma, colorectal cancer, connective tissue cancer, glioblastoma multiforme, uterus cervical cancer, uterine cancer, ovarian cancer and breast cancer.

[16] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate disclosed embodiments and together with the description serve to explain the principles of the disclosed embodiments. In the drawing,
[17] Figure 1 illustrates the androgen receptor (AR) degrading activity of compounds 2-22 and 2-32 in LNCAP cell lines 24 hours after administration using Western blot analysis.

Justice

[18] "Cancer" as used herein refers to diseases, disorders and conditions involving abnormal cell growth that has the potential to invade or spread to other parts of the body. Exemplary cancers include, but are not limited to, prostate cancer, head and neck cancer, skin cancer, sarcoma, renal cell carcinoma, adrenocortical carcinoma, bladder cancer, lung cancer, gastric carcinoma, esophageal carcinoma, pancreatic adenocarcinoma, colorectal cancer, connective tissue cancer, glioblastoma multiforme, cervical cancer, uterine cancer, ovarian cancer and breast cancer.

[19] As used herein, the term “androgen receptor positive” means that the androgen receptor is detected by one or more analytical methods, for example, immunohistochemistry. For example, a biopsy analysis of a subject's tumor may indicate the presence of androgen receptors. AR status can be tested by circulating cancer cells or circulating tumor DNA in blood tests. In some situations, AR testing may not be performed.

[20] "Subject" refers to an animal, such as a mammal, which has been or will be the subject of treatment, observation, or experimentation. The methods described herein may be useful for both human therapy and veterinary applications. In one embodiment, the subject is a human.

[21] "Treatment" or "treating" as used herein refers to an amelioration of a disease or disorder, or at least one recognizable symptom thereof. In another embodiment, “treatment” or “treating” refers to an improvement in at least one measurable physical parameter that is not necessarily perceived by the patient. In another embodiment, “treatment” or “treating” means that the progression of a disease or disorder is physically (eg, stabilizing perceptible symptoms), physiologically (eg, stabilizing a bodily variable), or It shows inhibition in both. In another embodiment, "treatment" or "treating" refers to delaying the onset of a disease or disorder.

[22] A dash ("-") not between two letters or symbols is used to indicate a point of attachment to a substituent. For example, -CN is attached through a carbon atom.

[23] "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where the event or circumstance does not occur . With respect to any group containing one or more substituents, it will be understood by those skilled in the art that such groups are not intended to introduce any substitution or substitution pattern that is sterically impractical, synthetically impractical and/or inherently labile. .

[24] When a range of values is recited, it is intended to include each value and sub-range within that range. For example, “C ₁ -C ₆ alkyl” means C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C _1-6 , C _1-5 , C _1-4 , C _1-3 . , C _1-2 , C _2-6 , C _2-5 , C _2-4 , C _2-3 , C _3-6 , C _3-5 , C _3-4 , C _4-6 , C _4-5 and C _5-6 alkyl.

[25] As used herein, the term “alkenyl” refers to an unsaturated, two-carbon group having a carbon-carbon double bond and refers herein to C ₂ -alkenyl.

[26] As used herein, the term “alkoxy” refers to an alkyl or cycloalkyl covalently bonded to an oxygen atom.

[27] As used herein, the term "alkyl" refers to a straight chain or branched group of 1-8 carbon atoms referred to herein as a saturated straight chain or branched hydrocarbon, such as (C ₁ -C ₈ )alkyl. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2 -Methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3 -Methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t- butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl and octyl. In some embodiments, “alkyl” is a straight chain hydrocarbon. In some embodiments, “alkyl” is a branched hydrocarbon.

[28] As used herein, the term “alkynyl” refers to an unsaturated two-carbon group having a carbon-carbon triple bond, denoted herein as C ₂ -alkynyl.

[29] As used herein, the term “aryl” refers to mono-, bi- or other multi-carbocyclic aromatic ring systems having 5 to 14 ring atoms. An aryl group may be optionally fused to one or more rings selected from aryl, cycloalkyl, heteroaryl and heterocyclyl. Aryl groups of the present disclosure include alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl , heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. Exemplary aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7,8- tetrahydronaphthyl. Exemplary aryl groups also include, but are not limited to, monocyclic aromatic ring systems in which the ring contains 6 carbon atoms, referred to herein as “C ₆ -aryl”.

[30] As used herein, the term “cycloalkyl” refers to a saturated 3-8 carbons derived from a cycloalkane (referred to herein as “(C ₃ -C ₈ )cycloalkyl”) or 3-16 carbons saturated. or an unsaturated cyclic, bicyclic or bridged bicyclic hydrocarbon group. Exemplary cycloalkyl groups include, but are not limited to, cyclohexane, cyclohexene, cyclopentane and cyclopentene. Cycloalkyl groups are alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl , heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. Cycloalkyl groups can be fused to other cycloalkyl (saturated or partially unsaturated), aryl or heterocyclyl groups to form bicyclic, tetracyclic, and the like. The term “cycloalkyl” also includes bridged, spiro-fused cyclic structures that may or may not contain heteroatoms.

[31] The term "halo" or "halogen" as used herein refers to -F, -Cl, -Br and/or -I.

[32] As used herein, the term “haloalkyl group” refers to an alkyl group substituted with one or more halogen atoms.

[33] As used herein, the term “heteroaryl” refers to mono-, bi- or other multi-cyclic aromatic containing one or more heteroatoms, eg, 1-4 heteroatoms such as nitrogen, oxygen and sulfur. Represents a ring system. Heteroaryl is alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl , heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. Heteroaryl may also be fused to a non-aromatic ring. Illustrative examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)- and (1, 2,4)-triazolyl, pyrazinyl, pyrimidyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, furyl, phenyl, isoxazolyl and oxazolyl. Exemplary heteroaryl groups include, but are not limited to, monocyclic aromatic rings, wherein the ring has 2-5 carbon atoms and 1-3 atoms, referred to herein as “(C ₂ -C ₅ )heteroaryl”. contains heteroatoms. In some embodiments, heteroaryl contains 5-10 ring atoms, 1-4 of which are heteroatoms selected from N, O, and S. In some embodiments, heteroaryl contains 5 to 8 ring atoms, 1 to 4 of which are heteroatoms selected from N, O, and S.

[34] The terms "heterocycle," "heterocyclyl" or "heterocyclic," as used herein, each contain 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur. represents a saturated or unsaturated 3 to 18 membered ring. A heterocycle may be aromatic (heteroaryl) or non-aromatic. Heterocycle is alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl , heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. Heterocycles also include bicyclic, tricyclic and tetracyclic groups in which either of said heterocyclic rings is fused to one or two rings independently selected from aryl, cycloalkyl and heterocycle. Exemplary heterocycles include acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, biotinyl, cinnolinyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, Dihydrothienyl, dithiazolyl, furyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolyl, isoquinolyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl , isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyridazinyl, pyri Dill, pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolidin-2-onyl, pyrrolinyl, pyrrolyl, quinolinyl, quinoxaloyl, tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydropyranyl , tetrahydroquinolyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolyl, thienyl, thiomorpholinyl, thiopyranyl and triazolyl. In some embodiments, a heterocycle contains 5 to 10 ring atoms, 1-4 of which are heteroatoms selected from N, O, and S. In some embodiments, a heterocycle contains 5 to 8 ring atoms, 1-4 of which are heteroatoms selected from N, O and S.

[35] As used herein, the terms "hydroxy" and "hydroxyl" refer to -OH.

[36] As used herein, the term “oxo” refers to a double bond to an oxygen atom (ie, =O). For example, when two geminal groups on a carbon atom are "taken together to form oxo," a carbonyl (ie, C=O) is formed.

[37] As used herein, the term "pharmaceutically acceptable carrier" refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, etc. compatible with the administration of the medicament. The use of such media and agents for pharmaceutically active substances is well known. The compositions may also contain other active compounds that provide supplemental, additive or enhanced therapeutic function.

[38] As used herein, the term “pharmaceutically acceptable salt” refers to a salt form of a compound of the present disclosure wherein the salt is non-toxic. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. For example, the "free base" form of a compound does not include ionic binding salts.

[39] The phrase “and pharmaceutically acceptable salts and deuterated derivatives thereof” refers to “and pharmaceutically acceptable salts and deuterated derivatives thereof” in reference to one or more compounds or formulas of the present disclosure. are used interchangeably with These phrases are intended to encompass pharmaceutically acceptable salts of any of the mentioned compounds, deuterated derivatives of any of the mentioned compounds, and pharmaceutically acceptable salts of these deuterated derivatives.

[40] One of ordinary skill in the art will recognize that when an amount of "a compound or a pharmaceutically acceptable salt thereof" is disclosed, the amount of the pharmaceutically acceptable salt form of the compound is an amount equal to the concentration of the free base of the compound. It should be noted that the disclosed amounts of a compound or a pharmaceutically acceptable salt thereof herein are based on its free base form.

[41] Suitable pharmaceutically acceptable salts are, for example, those disclosed in SM Berge, et al. J. Pharmaceutical Sciences , 1977, 66 , 1-19. For example, Table 1 of this article provides the following pharmaceutically acceptable salts:

Table 1:

[42] Non-limiting examples of pharmaceutically acceptable acid addition salts include salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid or perchloric acid; salts formed with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid; and salts formed using other methods used in the art, such as ion exchange. Non-limiting examples of pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclo Pentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulphate, heptanoate, hexanoate, hydroiodide , 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, maleate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, Nicotinate, nitrate, palate persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfo nate, undecanoate, and valerate salts. Pharmaceutically acceptable salts derived from suitable bases include alkali metal, alkaline earth metal, ammonium and N+(C _1-4 alkyl) ₄ salts. This disclosure also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Suitable non-limiting examples of alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium and magnesium. Further non-limiting examples of pharmaceutically acceptable salts use ammonium, quaternary ammonium, and counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates. and an amine cation formed by Other suitable, non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

[43] As used herein, nomenclature for compounds, including organic compounds, may be given using the common name for nomenclature, IUPAC, IUBMB or CAS recommendations. One of ordinary skill in the art can readily ascertain the structure of a compound by systematic reduction of the compound structure using a naming convention or given the compound name by commercially available software such as CHEMDRAW™ (Cambridgesoft Corporation, U.S.A.).

[44] The compounds of the present disclosure may contain one or more chiral centers and/or double bonds and thus exist as stereoisomers, such as geometric isomers, enantiomers or diastereomers. The term "stereoisomer" as used herein consists of all geometric isomers, enantiomers or diastereomers. Such compounds may be designated by the symbol "R" or "S" depending on the configuration of the substituents around the stereogenic carbon atom. This disclosure includes the various stereoisomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers. A mixture of enantiomers or diastereomers may be denoted by “(±)” in the nomenclature, but one of ordinary skill in the art will recognize that a structure may implicitly refer to a chiral center. In some embodiments, an enantiomer or stereoisomer may be provided that is substantially free of the corresponding enantiomer.

[45] In some embodiments, the compound is a racemic mixture of the (S)-isomer and the (R)-isomer. In another embodiment, provided herein is a mixture of compounds, wherein the individual compounds of the mixture are predominantly in the (S)- or (R)-isomeric configuration. For example, a mixture of compounds can be about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97% , has an (S)-enantiomer in excess of about 98%, about 99%, about 99.5% or greater. In other embodiments, the compound mixture is greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, about 97 % to greater than about 99.5%, greater than about 98% to about 99.5%, greater than about 99% to about 99.5%, or greater than the (S)-enantiomer. In other embodiments, the compound mixture is about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97 %, about 98%, about 99%, greater than about 99.5% or greater (R)-enantiomeric purity. In some other embodiments, the compound mixture is greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, about (R)-enantiomer in excess of greater than 97% to about 99.5%, greater than about 98% to about 99.5%, greater than about 99% to about 99.5%, or greater.

[46] Individual stereoisomers of the compounds of the present disclosure can be prepared by synthesis from commercially available starting materials containing asymmetric or stereogenic centers, followed by preparation of racemic mixtures by resolution methods well known to those skilled in the art. have. These resolution methods include (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography, and liberation of an optically pure product from the auxiliary; (2) salt formation with optically active dissolving agents; or (3) direct separation of a mixture of optical enantiomers on a chiral chromatography column. Stereoisomeric mixtures can also be resolved into their component stereoisomers by well-known methods such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallization of the compound as a chiral salt complex or crystallization of the compound in a chiral solvent. can Stereoisomers can also be obtained by well-known asymmetric synthetic methods from stereomerically pure intermediates, reagents and catalysts.

[47] Geometric isomers may also exist in the compounds of the present disclosure. This disclosure includes the various geometric isomers and mixtures thereof that result from substituent configurations around carbon-carbon double bonds or substituent configurations around carbocyclic rings. Substituents around a carbon-carbon double bond are indicated as being in the " Z " or " E " configuration, where the terms " Z " or " E " are used according to IUPAC standards. Unless otherwise specified, structures depicting double bonds include both the " E " and " Z " isomers.

[48] Alternatively, a substituent around a carbon-carbon double bond may be referred to as "cis" or "trans", where "cis" refers to a substituent on the same side of the double bond, and "trans" refers to the double bond represents a substituent on the opposite side of The arrangement of substituents around a carbocyclic ring is indicated as “cis” or “trans”. The term “cis” denotes substituents on the same side of the ring plane and the term “trans” denotes substituents on the opposite side of the ring plane. Mixtures of compounds in which substituents are placed on both the same and opposite sides of the plane of the ring are denoted "cis/trans".

[49] The compounds described herein may exist as tautomers, and although only one tautomeric structure is depicted, both tautomeric forms are intended to be included within the scope of the present disclosure.

[50] Further, unless otherwise stated, structures described herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having this structure that exclude replacement of a hydrogen with deuterium ( ² H) or tritium ( ³ H) or replacement of a carbon with a ¹³ C- or ¹⁴ C-carbon atom are within the scope of the present disclosure. . Such compounds may be useful, for example, as analytical tools, probes in biological assays, or therapeutic agents.

compound

[51] In some embodiments, provided herein are compounds of Formula (1), or tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, and deuterated derivatives of any of these:

In the above formula:

X ₁ is CR ₁ or N;

X ₂ is CR ₂ or N;

X ₃ is CR ₃ or N;

X ₄ is CR ₄ or N;

each of R ₁ , R ₂ , R ₃ , and R ₄ is independently selected from hydrogen, halogen, C ₁ -C ₃ alkoxy, and C ₁ -C ₃ haloalkyl, each of which is 0, 1, 2, or 3 substituted with R _S ;

each R ₅ is independently selected from halogen, hydroxyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl, —N(R ₉ ) ₂ , and —CN, which are each is substituted with 0, 1, 2, or 3 R _S ;

each R ₆ is independently selected from hydrogen, halogen, C ₁ -C ₃ alkyl, and C ₁ -C ₃ haloalkyl, each of which is substituted with 0, 1, 2, or 3 R _S ; two R ₆ groups taken together form oxo;

each R ₇ is independently selected from halogen, hydroxyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl, —N(R ₉ ) ₂ , and —CN, which are each is substituted with 0, 1, 2, or 3 R _S ;

each R ₈ is independently selected from hydrogen, hydroxyl, C ₁ -C ₃ alkyl, and C ₁ -C ₃ haloalkyl, each of which is substituted with 0, 1, 2, or 3 R _S ; two R ₈ groups taken together form oxo;

each R ₉ is independently hydrogen, C ₁ -C ₃ alkyl, -C(=O)-(C ₁ -C ₃ alkyl), -C(=O)-O-(C ₁ -C ₃ alkyl), and -C(=O)-NH-(C ₁ -C ₃ alkyl), each of which is substituted with 0, 1, 2, or 3 R _S ; two R ₉ groups taken together form a 3-6 membered heterocycle or heteroaryl;

each R _s is independently selected from halogen, hydroxyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl, —N(R ₉ ) ₂ , and —CN,

L is a linker of 1 to 16 carbon atoms in length, wherein at least one carbon atom is C(O), O, N(R ₉ ), S, C ₂ -alkenyl, C ₂ -alkynyl, cycloalkyl, aryl , heterocycle, or heteroaryl, wherein R ₉ , C ₂ -alkenyl, cycloalkyl, aryl, heterocycle, and heteroaryl are each independently substituted with 0, 1, 2, or 3 R _S become;

m is 0, 1, or 2;

n is 0, 1, 2, or 3;

o is 0, 1, 2, or 3.

[52] In some embodiments, the compound of formula (1) may be a compound of formula (1A):

[53] In some embodiments, X ₁ is N. In some embodiments, X ₂ is N. In some embodiments, X ₁ and X ₂ are each N. In some embodiments, X ₂ is CR ₂ , X ₃ is CR ₃ , and X ₄ is CR ₄ . In some embodiments, R ₂ , R ₃ , and R ₄ are each independently selected from H and F. In some embodiments, X ₂ is CR ₂ , X ₃ is CR ₃ , X ₄ is CR ₄ , and R ₂ , R ₃ , and R ₄ are each independently selected from H and F In some embodiments, X ₁ is CR ₁ , X ₂ is CR ₂ , X ₃ is CR ₃ , and X ₄ is CR ₄ . In some embodiments, R ₁ , R ₂ , R ₃ , and R ₄ are each independently selected from H and F. In some embodiments, X ₁ is CR ₁ , X ₂ is CR ₂ , X ₃ is CR ₃ , X ₄ is CR ₄ , and R ₁ , R ₂ , R ₃ , and R ₄ are each independently H and F.

[54] In some embodiments, R ₁ is F. In some embodiments, R ₂ is F. In some embodiments R ₃ is F. In some embodiments R ₄ is F. In some embodiments R ₁ and R ₃ are each F. In some embodiments, R ₃ and R ₄ are each F. In some embodiments, R ₂ , R ₃ , and R ₄ are each H. In some embodiments, R ₁ , R ₃ , and R ₄ are each H. In some embodiments, R ₁ , R ₂ , and R ₄ are each H. In some embodiments, R ₁ , R ₂ , and R ₃ are each H. In some embodiments, R ₂ and R ₄ are each H. In some embodiments, R ₁ and R ₂ are each H.

기는

[55] In some embodiments,

creeper

로부터 선택된다. 일부 구현예에서,

기는

이다. 일부 구현예에서,

기는

이다. 일부 구현예에서,

기는

이다. 일부 구현예에서,

기는

이다. 일부 구현예에서,

기는

이다. 일부 구현예에서,

기는

및

이다. 일부 구현예에서,

기는

이다.

is selected from In some embodiments,

creeper

to be. In some embodiments,

creeper

to be. In some embodiments,

creeper

to be. In some embodiments,

creeper

to be. In some embodiments,

creeper

to be. In some embodiments,

creeper

and

to be. In some embodiments,

creeper

to be.

[56] In some embodiments, each R ₅ is independently selected from halogen, C ₁ -C ₃ alkoxy, and C ₁ -C ₃ haloalkyl. In some embodiments, each R ₅ is independently selected from —Cl, —OCH ₃ , and —CF ₃ .

[57] In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1.

[58] In some embodiments, o is 0 or 1. In some embodiments, o is 0. In some embodiments, o is 1.

[59] In some embodiments, m and o are each 0.

[60] In some embodiments, each R ₆ is independently selected from H and C ₁ -C ₃ alkyl. In some embodiments, each R ₆ is independently selected from H and —CH ₃ . In some embodiments, one R ₆ is H and the other R ₆ is —CH ₃ . In some embodiments, each R ₆ is the same. In some embodiments, each R ₆ is different.

기는

[61] In some embodiments,

creeper

로부터 선택된다. 일부 구현예에서,

기는

이다. 일부 구현예에서,

기는

이다. 일부 구현예에서,

기는

이다. 일부 구현예에서,

기는

이다.

is selected from In some embodiments,

creeper

to be. In some embodiments,

creeper

to be. In some embodiments,

creeper

to be. In some embodiments,

creeper

to be.

기는

[62] In some embodiments,

creeper

으로부터 선택된다. 일부 구현예에서,

기는

이다. 일부 구현예에서,

기는

이다. 일부 구현예에서,

기는

이다. 일부 구현예에서,

기는

이다. 일부 구현예에서,

기는

이다. 일부 구현예에서,

기는

다. 일부 구현예에서,

기는

이다. 일부 구현예에서,

기는

이다.

is selected from In some embodiments,

creeper

to be. In some embodiments,

creeper

to be. In some embodiments,

creeper

to be. In some embodiments,

creeper

to be. In some embodiments,

creeper

to be. In some embodiments,

creeper

All. In some embodiments,

creeper

to be. In some embodiments,

creeper

to be.

[63] In some embodiments, each R ₇ is independently selected from halogen, hydroxyl, C ₁ -C ₃ alkyl, and C ₁ -C ₃ haloalkyl. In some embodiments, each R ₇ is independently selected from halogen, hydroxyl, —CH ₃ , and —CF ₃ . In some embodiments, each R ₇ is independently selected from F, hydroxyl, —CH ₃ , and —CF ₃ . In some embodiments, each R ₇ is independently F.

[64] In some embodiments, n is 0. In some embodiments, n is 1.

[65] In some embodiments, each R ₈ is hydrogen or two R ₈ groups are taken together to form oxo. In some embodiments, each R ₈ is hydrogen. In some embodiments, two R ₈ groups are taken together to form oxo.

기는

이다. 일부 구현예에서,

기는 [66] In some embodiments,

creeper

to be. In some embodiments,

creeper

로부터 선택된다. 일부 구현예에서,

기는

이다. 일부 구현예에서,

기는

이다. 일부 구현예에서,

기는

이다. 일부 구현예에서,

기는

이다. 일부 구현예에서,

기는

이다. 일부 구현예에서,

기는

이다. 일부 구현예에서,

기는

이다. 일부 구현예에서,

기는

이다. 일부 구현예에서, 일부 구현예에서,

기는

이다. 일부 구현예에서,

기는

이다. 일부 구현예에서,

기는

이다. 일부 구현예에서,

기는

이다. 일부 구현예에서,

기는

이다. 일부 구현예에서,

기는

이다.

is selected from In some embodiments,

creeper

to be. In some embodiments,

creeper

to be. In some embodiments,

creeper

to be. In some embodiments,

creeper

to be. In some embodiments,

creeper

to be. In some embodiments,

creeper

to be. In some embodiments,

creeper

to be. In some embodiments,

creeper

to be. In some embodiments, in some embodiments,

creeper

to be. In some embodiments,

creeper

to be. In some embodiments,

creeper

to be. In some embodiments,

creeper

to be. In some embodiments,

creeper

to be. In some embodiments,

creeper

to be.

[67] In some embodiments, each R ₉ is independently selected from hydrogen, C ₁ -C ₃ alkyl, and —C(=O)—C ₁ -C ₃ alkyl. In some embodiments, each R ₉ is independently selected from hydrogen and C ₁ -C ₃ alkyl. In some embodiments, each R ₉ is independently selected from hydrogen, —CH ₃ , —CH ₂ CH ₃ , and —CH(CH ₃ ) ₂ .

[68] In some embodiments, L is a linker from 1 to 12 carbon atoms in length, wherein one or more carbon atoms are C(=O), O, N(R ₉ ), S, C ₂ -alkenyl, C optionally replaced with ₂ -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl, wherein R ₉ , C ₂ -alkenyl, cycloalkyl, aryl, heterocycle and heteroaryl are each independently 0, 1, 2 or 3 R _S . In some embodiments, L is a linker from 1 to 10 carbon atoms in length, wherein one or more carbon atoms are C(=O), O, N(R ₉ ), S, C ₂ -alkenyl, C ₂ -alky. optionally replaced by nyl, cycloalkyl, aryl, heterocycle or heteroaryl, wherein R ₉ , C ₂ -alkenyl, cycloalkyl, aryl, heterocycle and heteroaryl are each independently 0, 1, 2 or 3 R replaced by _S. In some embodiments, L is a linker of 1 to 8 carbon atoms in length, wherein one or more carbon atoms are C(=O), O, N(R ₉ ), S, C ₂ -alkenyl, C ₂ -alky optionally replaced by nyl, cycloalkyl, aryl, heterocycle or heteroaryl, wherein R ₉ , C ₂ -alkenyl, cycloalkyl, aryl, heterocycle and heteroaryl are each independently 0, 1, 2 or 3 R replaced by _S. In some embodiments, L is a linker from 1 to 6 carbon atoms in length, wherein one or more carbon atoms are C(=O), O, N(R ₉ ), S, C ₂ -alkenyl, C ₂ -alky optionally replaced by nyl, cycloalkyl, aryl, heterocycle or heteroaryl, wherein R ₉ , C ₂ -alkenyl, cycloalkyl, aryl, heterocycle and heteroaryl are each independently 0, 1, 2 or 3 R replaced by _S.

[69] In some embodiments, one or more carbon atoms of linker L are optionally replaced with C(=O), O, N(R ₉ ), S, cycloalkyl, aryl, heterocycle, or heteroaryl. In some embodiments, one or more carbon atoms of linker L are optionally replaced with O, N(R ₉ ), cycloalkyl or heterocycle, wherein R ₉ , cycloalkyl and heterocycle are each independently 0, 1, 2, or 3 substituted with R _S . In some embodiments, at least one carbon atom of linker L is replaced by a heterocycle substituted with 0, 1, 2 or 3 R _S . In some embodiments, at least two carbon atoms of linker L are replaced by heterocycles each substituted with 0, 1, 2 or 3 R _S .

로부터 선택된다. [70] In some embodiments, the heterocycle of L is selected from piperidine and piperazine, each substituted with 0, 1, 2, or 3 R _S . In some embodiments, the heterocycle of L is

is selected from

[71] In some embodiments, L is

is selected from

[72] In some embodiments, provided herein are pharmaceutically acceptable salts of compounds of Formula (1). In some embodiments, provided herein are deuterated derivatives of pharmaceutically acceptable salts of compounds of Formula (1). In some embodiments, provided herein is a compound of Formula (1). In some embodiments, provided herein is a compound of Formula (1A).

[73] In some embodiments, provided herein is a compound selected from the compounds listed in Table 2, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a deuterated derivative of any of these.

Table 2. Exemplary compounds of the present disclosure

pharmaceutical composition

[74] The pharmaceutical composition of the present disclosure comprises at least one compound of Formula (1) (eg, Formula (1A)) formulated with a pharmaceutically acceptable carrier, or a tautomer, stereoisomer, or pharmaceutical thereof. commercially acceptable salts, or deuterated derivatives of any of these. Such formulations include those suitable for oral, rectal, topical, buccal, and parenteral (eg, subcutaneous, intramuscular, intradermal, or intravenous) administration. The most suitable dosage form in any given case will depend on the extent and severity of the condition being treated and the nature of the particular compound employed.

[75] Formulations suitable for oral administration are as powders or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion, as discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of a compound of the present disclosure. As indicated, such formulations may be prepared by any suitable pharmaceutical method comprising the step of bringing into association at least one compound of the present disclosure as the active compound and a carrier or excipient (which may constitute one or more accessory ingredients). . The carrier must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient. The carrier may be in solid or liquid form, or both, and is disclosed herein as the active compound in unit-dose formulations, e.g., tablets, which may contain from about 0.05% to about 95% by weight of at least one active compound. It can be formulated with at least one compound described. Other pharmacologically active substances, including other compounds, may also be present. The formulations of the present disclosure may be prepared by any well-known pharmaceutical technique consisting essentially of the mixing of the ingredients.

[76] For solid compositions, conventional non-toxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, and magnesium carbonate. etc. Pharmaceutically administrable compositions in liquid form, for example, include at least one active compound of the present disclosure as described herein and an optional pharmaceutical adjuvant, for example, in water, saline, aqueous dextrose, glycerol, and by dissolving or dispersing, for example, in an excipient such as ethanol, thereby forming a solution or suspension. In general, suitable formulations can be prepared by uniformly and intimately admixing at least one active compound of the present disclosure with a liquid or finely divided solid carrier, or both, followed by, if necessary, shaping of the product. For example, tablets may be prepared by compressing or molding powders or granules of at least one compound of the present disclosure, which may optionally be combined with one or more accessory ingredients. Compressed tablets may contain, in a suitable machine, at least one compound of the present disclosure in a free flowing form, such as a powder or granules, which may optionally be mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent(s). It can be prepared by compression. Molded tablets may be made by molding in a suitable machine, wherein the powder form of at least one compound of the present disclosure may be moistened with an inert liquid diluent.

[77] Formulations suitable for oral (sublingual) administration include lozenges comprising at least one compound of the present disclosure in a flavor-based, usually sucrose and acacia or tragacanth, and an inert-based, such as gelatin and glycerin or pastilles comprising at least one compound of sucrose and acacia.

[78] Formulations of the present disclosure suitable for parenteral administration include at least one compound of Formula (1) (eg, Formula (1A)), or a tautomer, stereo sterile aqueous preparations of isomers, pharmaceutically acceptable salts, or deuterated derivatives of any of these. Although these formulations are administered intravenously, administration may also be by subcutaneous, intramuscular, or intradermal injection. Such formulations can typically be prepared by admixing at least one compound described herein with water and rendering the resulting solution sterile and isotonic with blood. Injectable compositions according to the present disclosure may contain from about 0.1 to about 5% w/w of active compound.

[79] Formulations suitable for rectal administration are presented as unit-dose suppositories. They may be prepared by mixing at least one compound as described herein with one or more conventional solid carriers, such as cocoa butter, and then molding the resulting mixture.

[80] Formulations suitable for topical application to the skin may take the form of ointments, creams, lotions, pastes, gels, sprays, aerosols, or oils. Carriers and excipients that may be used include petrolatum, lanolin, polyethylene glycol, alcohols, and combinations of two or more thereof. active compound (i.e., at least one compound of formula (1) (e.g., formula (1A)), or a tautomer, stereoisomer, pharmaceutically acceptable salt, or deuterated derivative of any of these) is generally present in a concentration of from about 0.1% w/w to about 15% w/w, eg, from about 0.5% to about 2% w/w of the composition.

[81] The amount of active compound administered may depend on the subject being treated, the subject's body weight, the mode of administration and the discretion of the prescribing physician. For example, a dosing regimen may include daily or semi-daily administration of an encapsulated compound in a recognized dose of about 1 μg to about 1000 mg. In another embodiment, intermittent administration, such as monthly or yearly, of a dose of the encapsulated compound may be employed. Encapsulation facilitates access to the site of action and allows simultaneous administration of the active ingredients, resulting in a synergistic effect in theory. In accordance with standard dosing regimens, the physician will readily determine the optimal dosage and will be able to readily alter administration to achieve such dosage.

[82] A therapeutically effective amount of a compound or composition disclosed herein can be determined by the therapeutic effect of the compound. However, the dosage may vary depending on the requirements of the patient, the severity of the condition being treated, and the compound used. In one embodiment, a therapeutically effective amount of a disclosed compound is sufficient to establish a maximum plasma concentration. For example, borderline doses as determined by animal testing, and dose adjustments for human administration, are performed in accordance with state-of-the-art practice.

[83] Toxicity and therapeutic efficacy can be determined, for example, in cell culture or experimental animals, to determine the LD ₅₀ (lethal dose for 50% of the population) and ED ₅₀ (the therapeutically effective dose in 50% of the population). can be determined by standard pharmaceutical procedures. The dose ratio between toxic and therapeutic effects is the therapeutic index, which can be expressed as the ratio LD ₅₀ /ED ₅₀ . Compositions that exhibit large therapeutic indices are preferred.

[84] Data obtained from cell culture assays or animal studies can be used to formulate various dosages for use in humans. A therapeutically effective dosage achieved in one animal model can be converted for use in another animal, including humans, using transformation factors known in the art (eg, Freireich et al., Cancer Chemother). See Reports 50(4):219 244 (1966) and the table below for equivalent surface area dosage factors (Table 3).

Table 3. Equivalent surface area dose factors.

[85] The dosage of such compounds is preferably within a range of circulating concentrations that include the ED ₅₀ with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration employed. In general, a therapeutically effective amount will vary with the age, condition, and sex of the subject, as well as the severity of the subject's medical condition. The dosage is determined by the physician and, if necessary, can be adjusted to suit the therapeutic effect observed.

treatment method

[86] In some embodiments, a compound of Formula (1) (eg, Formula (1A)), or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, and deuterated derivatives of any of these is administered to treat cancer in a subject in need thereof. In some embodiments, the cancer is prostate cancer, head and neck cancer, skin cancer, sarcoma, renal cell carcinoma, adrenocortical carcinoma, bladder cancer, lung cancer, gastric carcinoma, esophageal carcinoma, pancreatic adenocarcinoma, colorectal cancer, connective tissue cancer, glioblastoma multiforme, uterus cervical cancer, uterine cancer, ovarian cancer and breast cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is skin cancer. In some embodiments, the cancer is a sarcoma. In some embodiments, the cancer is renal cell carcinoma. In some embodiments, the cancer is adrenocortical carcinoma. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is gastric carcinoma. In some embodiments, the cancer is esophageal carcinoma. In some embodiments, the cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is a connective tissue cancer. In some embodiments, the cancer is glioblastoma multiforme. In some embodiments, the cancer is cervical cancer. In some embodiments, the cancer is uterine cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is breast cancer.

[87] In some embodiments, the cancer is androgen receptor positive.

[88] In some embodiments, a compound of Formula (1) (eg, Formula (1A)), or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, and deuterated derivatives of any of these is administered as a pharmaceutical composition.

[89] In some embodiments, the subject has previously been treated with an anticancer agent. In some embodiments, the anticancer agent is enzalutamide, apalutamide, bicalutamide, darolutamide, flutamide, abiratarone, or a combination of any of these. In some embodiments, the anticancer agent is enzalutamide.

[90] In some embodiments, disclosed herein is a compound of Formula (1) (eg, Formula (1A)), or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, for the treatment of cancer, and a pharmaceutically acceptable salt thereof provided is the use of a deuterated derivative of any of In some embodiments, the cancer is prostate cancer, head and neck cancer, skin cancer, sarcoma, renal cell carcinoma, adrenocortical carcinoma, bladder cancer, lung cancer, gastric carcinoma, esophageal carcinoma, pancreatic adenocarcinoma, colorectal cancer, connective tissue cancer, glioblastoma multiforme, uterus cervical cancer, uterine cancer, ovarian cancer and breast cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is skin cancer. In some embodiments, the cancer is a sarcoma. In some embodiments, the cancer is renal cell carcinoma. In some embodiments, the cancer is adrenocortical carcinoma. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is gastric carcinoma. In some embodiments, the cancer is esophageal carcinoma. In some embodiments, the cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is a connective tissue cancer. In some embodiments, the cancer is glioblastoma multiforme. In some embodiments, the cancer is cervical cancer. In some embodiments, the cancer is uterine cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is androgen receptor positive.

[91] In some embodiments, disclosed herein is a compound of Formula (1) (eg, Formula (1A)), or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt thereof, in the manufacture of a medicament. provided is the use of a deuterated derivative of any of In some embodiments, the medicament is for the treatment of cancer. In some embodiments, the cancer is prostate cancer, head and neck cancer, skin cancer, sarcoma, renal cell carcinoma, adrenocortical carcinoma, bladder cancer, lung cancer, gastric carcinoma, esophageal carcinoma, pancreatic adenocarcinoma, colorectal cancer, connective tissue cancer, glioblastoma multiforme, uterus cervical cancer, uterine cancer, ovarian cancer and breast cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is skin cancer. In some embodiments, the cancer is a sarcoma. In some embodiments, the cancer is renal cell carcinoma. In some embodiments, the cancer is adrenocortical carcinoma. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is gastric carcinoma. In some embodiments, the cancer is esophageal carcinoma. In some embodiments, the cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is a connective tissue cancer. In some embodiments, the cancer is glioblastoma multiforme. In some embodiments, the cancer is cervical cancer. In some embodiments, the cancer is uterine cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is androgen receptor positive.

[92] In some embodiments, contacting a cell with a compound of Formula (1) (eg, Formula (1A)), or a tautomer, stereoisomer, pharmaceutically acceptable salt, or deuterated derivative of any thereof A method of inhibiting cell growth comprising Sikkim is provided. In some embodiments, the cell is a cancer cell. In some embodiments, the cancer cell is a prostate cancer cell. In some embodiments, the cell is estrogen receptor positive.

[93] In one embodiment, a compound of Formula (1) (eg, Formula (1A)), or a tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate thereof, is administered in combination with another therapeutic agent. Other therapeutic agents may provide added or synergistic value over administration of a compound of the present disclosure alone. Therapeutic agents include, for example, hormones and hormone analogs; signal transduction pathway inhibitors; topoisomerase I inhibitors; topoisomerase II inhibitors; antimetabolites neoplasia; antibiotics; alkylating agents; anti-microtubule agents; platinum coordination complex; aromatase inhibitors; and anti-mitotic agents.

[94] In some embodiments, the therapeutic agent may be a hormone or a hormone analog. In some embodiments, the therapeutic agent may be a signal transduction pathway inhibitor. In some embodiments, the therapeutic agent can be a topoisomerase I inhibitor. In some embodiments, the therapeutic agent may be a topoisomerase II inhibitor. In some embodiments, the therapeutic agent can be an antimetabolic neoplasia. In some embodiments, the therapeutic agent may be an antibiotic neoplastic agent. In some embodiments, the therapeutic agent can be an alkylating agent. In some embodiments, the therapeutic agent can be an anti-microtubule agent. In some embodiments, the therapeutic agent can be a platinum coordination complex. In some embodiments, the therapeutic agent may be an aromatase inhibitor. In some embodiments, the therapeutic agent can be an anti-mitotic agent.

[95] In some embodiments, the aromatase inhibitor is from anastrazole, letrozole, vorozole, fadrozole, exemestane, and formestane. can be selected. In some embodiments, the aromatase inhibitor is anastrazole. In some embodiments, the aromatase inhibitor can be letrozole. In some embodiments, the aromatase inhibitor can be vorozol. In some embodiments, the aromatase inhibitor may be fadrozole. In some embodiments, the aromatase inhibitor may be exemestane. In some embodiments, the aromatase inhibitor may be formestane.

[96] In some embodiments, the anti-mitotic agent may be selected from paclitaxel, docetaxel, and Abraxane. In some embodiments, the anti-mitotic agent can be paclitaxel. In some embodiments, the anti-mitotic agent may be docetaxel. In some embodiments, the anti-mitotic agent can be Abraxane.

[97] In some embodiments, a compound of Formula (1) (eg, Formula (1A)), or a tautomer, stereoisomer, pharmaceutically acceptable salt, or deuterated derivative of any of these is It may be administered in combination with a hormone or a hormone analog. In some embodiments, a compound of formula (1), or a tautomer, stereoisomer, pharmaceutically acceptable salt, or deuterated derivative of any of these may be administered in combination with a signal transduction pathway inhibitor. In some embodiments, a compound of formula (1), or a tautomer, stereoisomer, pharmaceutically acceptable salt, or deuterated derivative of any of these can be administered in combination with an antimetabolites neoplastic agent. In some embodiments, a compound of formula (1), or a tautomer, stereoisomer, pharmaceutically acceptable salt, or deuterated derivative of any of these may be administered in combination with a topoisomerase I inhibitor. . In some embodiments, a compound of formula (1), or a tautomer, stereoisomer, pharmaceutically acceptable salt, or deuterated derivative of any of these may be administered in combination with a topoisomerase II inhibitor. . In some embodiments, a compound of formula (1), or a tautomer, stereoisomer, pharmaceutically acceptable salt, or deuterated derivative of any of these, may be administered in combination with an aromatase inhibitor.

Example

[98] The Examples and Preparations provided below further describe and exemplify the compounds as disclosed herein and methods for preparing the compounds. It should be understood that the scope of the present disclosure is not limited in any way by the scope of the following examples and preparations.

[99] The chemical entities described herein can be synthesized according to one or more exemplary schemes herein and/or techniques well known in the art. Unless otherwise specified, the reactions described herein occur at atmospheric pressure, typically within a temperature range of about -10°C to about 200°C. Also, except where otherwise specified, reaction times and conditions are intended to be approximate, eg, in a temperature range from about -10°C to about 200°C over a period that may be, for example, from about 1 to about 24 hours. is intended to occur at approximately atmospheric pressure within; In some embodiments, the reaction left to react overnight can be a duration of about 16 hours on average.

[100] Isolation and purification of the chemical entities and intermediates described herein may be carried out if desired by any suitable separation or purification procedure, such as filtration, extraction, crystallization, column chromatography, thin layer chromatography or thick layer chromatography, or these It can be performed by a combination of procedures. See, eg, Carey et al. Advanced Organic Chemistry, 3 ^rd Ed., 1990 New York: Plenum Press; Mundy et al., Name Reaction and Reagents in Organic Synthesis, 2 ^nd Ed., 2005 Hoboken, NJ: J. Wiley & Sons. Specific examples of suitable separation and isolation procedures are provided with reference to the Examples below. However, other equivalent separation or isolation procedures may also be used.

[101] It is well understood that, in all methods, protecting groups for sensitive or reactive groups may be employed if necessary in accordance with the general principles of chemistry. Protecting groups are engineered according to standard methods of organic synthesis (TW Greene and PGM Wuts (1999) Protective Groups in Organic Synthesis, 3 ^rd Ed., John Wiley & Sons). These groups can be removed at convenient steps of compound synthesis using methods readily apparent to those skilled in the art.

[102] If desired, the (R)-isomers and (S)-isomers of the non-limiting exemplary compounds, if present, can be separated by methods known to those skilled in the art, for example, by crystallization to form diastereomeric salts or complexes. by; through the formation of diastereomeric derivatives which can be separated, for example, by crystallization, gas-liquid or liquid chromatography; by selective reaction of one enantiomer with an enantiomer-specific reagent, for example, enzymatic oxidation or reduction followed by separation of the modified enantiomer and the unmodified enantiomer; or by gas-liquid or liquid chromatography with an attached chiral ligand or in the presence of a chiral solvent, for example, in a chiral environment on a chiral support such as silica. Alternatively, certain enantiomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric conversion.

[103] The compounds described herein can optionally be contacted with a pharmaceutically acceptable acid to form the corresponding acid addition salt. In addition, the compounds described herein may optionally be contacted with a pharmaceutically acceptable base to form the corresponding base addition salt.

[104] In some embodiments, the disclosed compounds can generally be synthesized by appropriate combinations of well-known synthetic methods. Techniques useful for synthesizing these chemical entities are readily apparent and accessible to those skilled in the art based on the present disclosure. Many optionally substituted starting compounds and other reactants are commercially available, for example, from Millipore Sigma, or can be readily prepared by one of ordinary skill in the art using commonly used synthetic methods.

[105] The following discussion is provided to illustrate specific methods of various methods for use in preparing the disclosed compounds, and is not intended to limit the scope of reactions or sequence of reactions that may be used to prepare the compounds provided herein. . One of ordinary skill in the art will understand that standard valences apply to all compounds or named compounds disclosed herein within a genus unless otherwise specified.

[106] All final compounds of the examples described herein were checked for purity by HPLC on Shimadzu LC-2010A and compounds were detected at wavelengths of 214 nM and 254 nM. Purity of all final compounds was greater than 95% based on HPLC peaks (214 nM and 254 nM wavelengths). Liquid chromatography conditions: column, XBRIDGE C18, 3.6 microns, 2.1 x 50 mm: mobile phase, water (0.05% TFA) and acetonitrile (0.05% TFA), 10% acetonitrile to 100% acetonitrile over 7 min. linear gradient; oven temperature 45°C; Flow rate, 0.8 mL/mL. H-NMR was obtained on a Bruker 400 MHz NMR spectrometer.

[107] List of Abbreviations

[108] ACN: acetonitrile

[109] AcOH: acetic acid

[110] BSA: Benzenesulfonic acid

[111] DCM: dichloromethane

[112] DEAD: N,N-diethyl azodicarboxylate

[113] DIEA: diisopropylethylamine

[114] DMF: N,N-dimethylformamide

[115] DMAP: 4-dimethylaminopyridine

[116] DMSO: dimethyl sulfoxide

[117] EA: ethyl acetate

[118] HATU; O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[119] HPLC: High Performance Liquid Chromatography

[120] HRMS: High-Resolution Mass Spectrometry

[121] IBX: 2-iodoxybenzoic acid

[122] LC/MS: Liquid Chromatography Mass Spectrometry

[123] MW: microwave

[124] NMI: N-methylimidazole

[125] NMP: N-methyl-2-pyrrolidone

[126] NMR: nuclear magnetic resonance

[127] PTSA: p-toluenesulfonic acid

[128] TCFH: N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate

[129] TEA: triethylamine

[130] THF: tetrahydrofuran

[131] TLC: thin layer chromatography

[132] Prep-TLC; Preparative Thin Layer Chromatography

[133] TFA: trifluoroacetic acid

General Synthesis Scheme

[134] The compound of formula (1) (eg, formula (1A); see the compound of Table 2) can be prepared according to the following scheme. The following schemes represent the general methods used to prepare these compounds. However, the synthesis of these compounds is not limited to these representative methods, as they may be prepared by those skilled in the art of synthetic chemistry in a variety of other methods, for example, stepwise or modular.

Scheme 1: Synthesis of 2-1.

[135] Compound 2-2 can be synthesized according to the method described in Scheme 1.

Scheme 2: Synthesis of 2-6.

[136] Compounds 2-3, 2-4, and 2-5 can be prepared according to methods analogous to those described in Scheme 2.

Scheme 3: Synthesis of 2-7.

Scheme 4: Synthesis of 2-13.

[137] Compounds 2-14, 2-15, 2-16, and 17 can be synthesized according to methods analogous to those described in Scheme 4.

Scheme 5: Synthesis of 2-18.

[138] Compounds 2-19, 2-20, and 2-46 can be synthesized through the same method.

Scheme 6: Synthesis of 2-22.

[139] The same method can be used to synthesize 2-21.

Scheme 7: Synthesis of 2-43.

[140] Compounds 2-23, 2-24, 2-25, 2-26, 2-27, and 2-28 can be prepared using analogous synthetic routes.

Scheme 8: Synthesis of 2-32.

[141] The following compounds can be synthesized according to synthetic methods similar to those described in Scheme 6: 2-29, 2-30, 2-31, 2-33, 2-34, and 2-49.

Scheme 9: Synthesis of 2-11.

[142] The following compounds can be synthesized according to synthetic methods similar to those described in Scheme 9: 2-8, 2-9, 2-10, 2-12 and 2-44.

Scheme 10: Synthesis of 2-36.

[143] Compounds 2-35, 2-47, 2-48 and 2-50 can be synthesized using the same method.

Scheme 11: Synthesis of 2-37.

[144] Compounds 2-38, 2-39 and 2-40 can be prepared using the same route as described in Scheme 11.

Scheme 12: Synthesis of 2-41 and 2-42.

Scheme 13: Synthesis of 2-45.

Preparation of intermediates

Synthesis of trans-5-[3-amino-2,2,4,4-tetramethylcyclobutoxy)]quinoline-8-carbonitrile hydrochloride (Intermediate 1-1)

Step 1: Preparation of 5-fluoroquinoline-8-carbonitrile

[145] 8-bromo-5-fluoroquinoline (2.00 g, 8.85 mmol, 1.00 eq), Pd(PPh ₃ ) ₄ (1.02 g, 884.7 umol, 0.10 eq) and Zn(CN) ₂ (2.01 g, 17.1 mmol, 1.08 mL, 1.93 eq) was placed in a microwave tube in DMF (20.0 mL). The sealed tube was heated at 150° C. for 0.5 h under microwave conditions. TLC (petroleum ether/ethyl acetate = 3/1, R _f (starting material) = 0.50, R _f (product) = 0.32) showed the starting material was consumed completely. The four reactions were repeated in parallel and the resulting reactants were combined for work-up. The mixture was poured into water (300.0 mL) and extracted with EtOAc (80.0 mL x 2). The combined organic layers were washed with brine (150.0 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography on silica gel eluting with petroleum ether/ethyl acetate (50/1 to 1/1) to give the title compound (3.20 g, 52.1% yield) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.18 (dd, J = 4.44, 1.65 Hz, 1 H), 8.52 (dd, J = 8.40, 1.65 Hz, 1 H), 8.14 (dd, J = 8.40, 5.51) Hz, 1 H), 7.64 (dd, J = 8.44, 4.30 Hz, 1 H), 7.32 (t, J = 8.40 Hz, 1 H).

Step 2: Preparation of tert-butyl trans-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)carbamate

[146] 5-fluoroquinoline-8-carbonitrile (1.60 g, 9.29 mmol, 1.00 eq) and trans-tert-butyl-3-hydroxy-2,2,4,4- in ACN (30.0 mL) To a solution of tetramethylcyclobutyl)carbamate (2.26 g, 9.29 mmol, 1.00 eq) was added Cs ₂ CO ₃ (6.06 g, 18.5 mmol, 2.00 eq) at 15° C., then the mixture was stirred at 100° C. for 4 h. stirred for a while. TLC (petroleum ether/ethyl acetate = 2/1, R _f (starting material) = 0.51, R _f (product) = 0.39) showed the starting material was consumed completely. The mixture was filtered, the cake was washed with EtOAc (30.0 mL), and the combined organic layers were concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with petroleum ether/ethyl acetate (50/1 to 1/1) to give the title compound (1.70 g, 46.3% yield) as a white solid.

Step 3: Preparation of trans-5-[3-amino-2,2,4,4-tetramethylcyclobutoxy)]quinoline-8-carbonitrile hydrochloride (Intermediate 1-1)

[147] tert-Butyl trans-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)carbamate (1.70) in DCM (10.0 mL) g, 4.30 mmol, 1.00 eq) was added HCl (g)/EtOAc (4.00 M, 30.0 mL, 27.9 eq) at 0° C. and the mixture was stirred for 0.5 h. TLC (petroleum ether/ethyl acetate = 2/1, R _f (starting material) = 0.53, R _f (product) = 0) showed the starting material was consumed completely. The mixture was filtered and the solid was washed with DCM (10.0 mL) and dried under vacuum to give the title compound (1.33 g, 92.4% yield, 99.1% purity) as a yellow solid of hydrochloride. LC/MS 296.3 (M+H)+; ¹ H NMR: (400 MHz, MeOD) δ 9.19 - 9.30 (m, 2 H), 8.42 (d, J = 8.40 Hz, 1 H), 8.04 (dd, J = 8.84, 5.2 Hz, 1 H), 7.21 (d, J = 8.44 Hz, 1 H), 4.70 (s, 1 H), 3.40 (s, 1 H), 1.48 (s, 6 H), 1.34 (s, 6 H).

Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione (Intermediate 1-2)

[148] Intermediate 1-2 was prepared according to the above scheme as the hydrochloride salt using a similar method described in the literature. LC/MS 343.1 [M+H] ⁺ ; ¹ H-NMR (400 MHz, CD ₃ OD) δ ppm 7.76 (d, J = 8.36 Hz, 1 H), 7.47 (s, 1 H), 7.35 (dd, J = 8.36, 1.54 Hz, 1 H), 5.09 (br dd, J = 12.8, 5.40 Hz, 1 H), 3.67 - 3.74 (m, 4 H), 3.37 - 3.42 (m, 4 H), 2.63 - 2.94 (m, 3 H), 2.07 - 2.17 ( m, 1 H).

of (S)-3-(6-fluoro-1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (intermediate 1-3) synthesis

Step 1: Preparation of methyl 2-bromo-4,5-difluorobenzoate.

Thionyl chloride (130 g, 1.09 mol) was added slowly to a mixture of 2-bromo-4,5-difluorobenzoic acid (200 g, 0.84 mol) in MeOH (600 mL) at 10 °C, the mixture was stirred at 80 The mixture was stirred at ℃ for 3 hours. TLC showed the reaction was complete. The mixture was cooled to room temperature, concentrated and partitioned between ethyl acetate and water. The organic layer was washed twice with saturated Na ₂ CO ₃ and brine, dried over Na ₂ SO ₄ and concentrated to crude methyl 2-bromo-4,5-difluorobenzoate (210 g, yield: 100 %), which was used in the next step without further purification.

Step 2: Preparation of tert-butyl 4-(5-bromo-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate.

Methyl 2-bromo-4,5-difluorobenzoate (210 g, 0.84 mol), tert-butyl piperazine-1-carboxylate (234 g) in N,N-dimethylacetamide (600 mL) , 1.25 mol) and K ₂ CO ₃ (173 g, 1.25 mol) was stirred at 80° C. for 16 h. TLC showed the reaction was complete. The mixture was added to water (2 L) and stirred for 10 min, then ethyl acetate was added. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, dried over brine, Na ₂ SO ₄ , and concentrated to tert-butyl 4-(5-bromo-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1 -Carboxylate (315.8 g, yield: 90%) was obtained.

Step 3: Preparation of tert-butyl 4-(5-cyano-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate.

tert-Butyl 4-(5-bromo-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (306 g, 0.73 mol) and CuCN in DMF (1.2 L) (98 g, 1.09 mol) was stirred at 100° C. for 16 h. TLC showed the reaction was complete. The mixture was cooled to room temperature. Ethyl acetate (2 L) and ammonium hydroxide (2 L) were added and the mixture was stirred for 30 min. The mixture was filtered. The organic layer was washed with water, dried over Na ₂ SO ₄ and concentrated to give the crude product (254 g). This crude product was taken up in petroleum ether (1 L) under reflux. The mixture was filtered and dried in an oven at 50° C. to obtain tert-butyl 4-(5-cyano-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (215 g , yield: 81%) was obtained.

Step 4: Preparation of tert-butyl 4-(2-fluoro-5-formyl-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate.

tert-Butyl 4-(5-cyano-2-fluoro-4-(methoxycarbonyl) in a solution of pyridine (391 g, 4.95 mol), water (200 mL), acetic acid (264 g, 4.4 mol) )Phenyl)piperazine-1-carboxylate (200 g, 0.55 mol) and Raney-nickel (85% in water, 100 g) were added at room temperature. The resulting mixture was heated to 60°C. Sodium hypophosphite (292 g in 500 mL water) was added dropwise to the mixture. The mixture was stirred at 60° C. for 16 h. TLC showed the reaction was not complete. The mixture was further stirred for 10 h. The mixture was cooled to room temperature. Ethyl acetate and water were added. The mixture was filtered. The organic layer was washed with water, dried over 1N HCl and brine, Na ₂ SO ₄ , and concentrated under reduced pressure to give the crude product (208 g, crude), which was further purified by a pad of silica-gel to 4- (2-Fluoro-5-formyl-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (86.5 g, yield: 43%) was provided.

Step 5: tert-Butyl (S)-4-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-6-fluoro-1 Preparation of -oxoisoindolin-5-yl)piperazine-1-carboxylate.

A solution of tert-butyl 4-(2-fluoro-5-formyl-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (81.5 g, 0.22 mol) in methanol (500 mL) was added tert-butyl (S)-4,5-diamino-5-oxopentanoate (54 g, 0.27 mol) at room temperature. Acetic acid (19.8 g, 0.33 mol) was added at 0° C. followed by slow addition of sodium cyanoborohydride (27.6 g, 0.44 mol). The mixture was stirred at room temperature for 16 h. TLC showed the reaction was complete. The mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was washed with saturated citric acid, brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product, which was further purified by a pad of silica gel to tert-butyl (S)-4-( 2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazin-1- Carboxylate (80 g, yield: 69%) was obtained.

Step 6: (S)-3-(6-Fluoro-1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione benzenesulfonic acid ( Preparation of intermediates 1-3).

(S)-4-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-6-fluoro-1 in acetonitrile (670 mL) To a solution of -oxoisoindolin-5-yl)piperazine-1-carboxylate (67 g, 0.13 mol) was added benzenesulfonic acid (43 g, 0.26 mol). The mixture was stirred at 80° C. for 16 h. LCMS showed the reaction was complete. The mixture was cooled to room temperature. The mixture was filtered and dried (S)-3-(6-fluoro-1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione benzene Sulfonic acid (56 g, 86%) was obtained as an off-white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 1.94-1.99 (m, 1H), 2.35-2.43 (m, 1H), 2.58-2.62 (m, 1H), 2.88-2.91 (m, 1H), 3.30 ( s, 8H), 4.38 (d, J = 17.2 Hz, 1H), 4.26 (d, J = 17.2 Hz, 1H), 5.08 (dd, J = 13.2, 5.2 Hz, 1H), 7.29-7.35 (m, 4H), 7.49 (d, J = 8.7 Hz, 1H), 7.60 (m, 2H), 8.72 (br s, 2H), 10.99 (s, 1H). LCMS m/z 347.3 [M+1] ⁺ .

Synthesis of (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidin-2,6-dione (Intermediate 1-4)

[149] (S)-tert-butyl 4-(2-(1-amino-5-tert-butoxy-1,5-dioxopentan-2-yl)-1 in acetonitrile (90 mL) -oxoisoindolin-5-yl)piperazine-1-carboxylate (5.8 g, 12 mol, prepared using the same method as described for Intermediate 1-3) in benzenesulfonic acid (3.64 g , 23 mol) was added. The mixture was stirred at 85° C. for 12 h. LC/MS showed the reaction was complete. The mixture was concentrated in vacuo. The residue was triturated with ethyl acetate (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione benzenesulfonate ( 5.2 g, 93%) as an off-white solid. LC/MS 329.1 [M+1] ⁺ ; ¹ H NMR (400 MHz, DMSO-d6) δ 1.95-1.99 (m, 1H), 2.36-2.41 (m, 1H), 2.58-2.62 (d, 1H), 2.88-2.91 (m, 1H), 3.26 ( s, 4H), 3.49-3.52 (m, 4H), 4.21-4.38 (dd, 2H), 5.05-5.10 (dd, 1H), 7.12-7.16 (m, 2H), 7.30-7.358 (m, 3H), 7.58-7.62 (m, 3H), 8.72 (s, 2H), 11.0 (s, 1H).

Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(piperazin-1-yl)isoindoline-1,3-dione (Intermediate 1-5)

[150] Intermediate 1-5 was prepared according to the above scheme as the hydrochloride salt. LC/MS 361.1 [M+1] ⁺ ; ¹ H NMR (400 MHz, DMSO-d6) δ 11.1 (s, 1 H), 9.49 (br s, 2 H), 7.79 (d, J = 11.2 Hz, 1 H), 7.57 (br d, J = 7.32) Hz, 1 H), 5.12 (br dd, J = 12.4, 5.32 Hz, 1 H), 3.50 (br s, 4 H), 3.24 (br s, 4 H), 2.80 - 2.95 (m, 1 H), 2.52 - 2.69 (m, 2 H), 1.97 - 2.10 (m, 1 H)

Preparation of Example Compounds

[151] All final compounds of the examples described in this section and in Table 2 were checked for purity by HPLC and the compounds were detected at wavelengths of 214 nM and 254 nM. Purity of all final compounds was greater than 95% based on HPLC peak analysis (214 nM and 254 nM wavelengths). H-NMR was obtained on a Bruker NMR spectrometer (400 MHz). LC/MS was performed on an Agilent 6125 under the following conditions: column, Waters CORTECS C18, 2.7 um, 4.6x30 mm; mobile phase, ACN (0.05% TFA) and water (0.05 TFA); Gradient: 5% ACN to 95% ACN in 1.0 min, hold 1.0 min, total 2.5 min; flow rate 1.8 mL/min; Column temperature 45°C. Analytical HPLC was performed on a SHIMADZU LC-2010A under the following conditions: column, XBRIDGE 3.5 um, 2.1x 50 mm; mobile phase, water (0.05% TFA) and ACN (0.05% TFA); gradient, 10% to 100% ACN over 7 min, hold 1 min; column oven temperature, 45° C.; Flow rate, 0.8 mL/min.

Example 1: N-((1,3-trans)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4 -((((1r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)( Synthesis of methyl)amino)methyl)piperidin-1-yl)nicotinamide (2-9)

Step 1: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione

To a solution of 3-aminopiperidine-2,6-dione hydrochloride (8.7 g, 52.5 mmol) in acetic acid (350 mL) stirred at room temperature under nitrogen (5-hydroxyisobenzofuran-1,3-dione ( 8.7 g, 52.5 mmol) and Et ₃ N (11.7 g, 115.5 mmol) were added. Then, the reaction mixture was stirred at 120° C. for 3 hours. The reaction mixture was cooled to room temperature and filtered to give the crude product. The crude product was stirred in water (50 mL) for 1 h, filtered, washed with water (20 mL) and dried to give the desired product (11.4 g, 5.4 mmol, 79% yield) as a yellow solid. LC/MS: 274.8 [M+1] ⁺ .

Step 2: tert-Butyl ((1,3-trans)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl) Preparation of oxy)cyclobutyl)carbamate

2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (5.7 g, 20.8 mmol) in THF (50 mL) stirred at 60° C. under hydrogen, _DEAD (4.3 g; 24.9 mmol) was added. The reaction mixture was stirred at 60° C. for 3 hours. The reaction mixture was filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (DCM:MeOH=10:1) to give the crude product (11 g, 17.4 mmol, 70% purity, 83% yield) as a yellow solid.

Step 3: Preparation of 5-((1,3-trans)-3-aminocyclobutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

tert-Butyl ((1,3-trans)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5 in DCM (30 mL)) To a solution of -yl)oxy)cyclobutyl)carbamate (11 g, 17.4 mmol, 70% purity) was added TFA (10 mL). The reaction mixture was stirred at room temperature for 3 h and evaporated in vacuo to give the crude product. The crude product was worked up and purified by silica gel chromatography (DCM:MeOH=10:1) to give the desired product (1.4 g, 4 mmol, 23 % yield) as a red solid. LC/MS: 343.9 [M+1] ⁺ .

Step 4: Preparation of tert-butyl 6-(4-(hydroxymethyl)piperidin-1-yl)nicotinate

A mixture of tert-butyl 6-chloronicotinate (500 mg, 2.35 mmol), piperidin-4-ylmethanol (297 mg, 2.58 mmol) and DIEA (606 mg, 4.70 mmol) in DMSO (10 mL) was taken Stir overnight at 100°C. TLC showed the reaction was complete. The mixture was partitioned between EA and H ₂ O. The organic phase was washed with brine, dried over magnesium sulfate and evaporated to dryness. The crude product was purified by silica gel chromatography (10-50% EtOAc in hexanes as eluent) to give the desired compound (400 mg, 58.3%). LC/MS: 293.2 [M+H] ⁺ .

Step 5: Preparation of tert-butyl 6-(4-formylpiperidin-1-yl)nicotinate

A mixture of tert-butyl 6-(4-(hydroxymethyl)piperidin-1-yl)nicotinate (574 mg, 1.97 mmol) and IBX (658 mg, 2.35 mmol) in DMSO (10 mL) was Stir overnight at 50°C. TLC showed the reaction was complete. The mixture was partitioned between EA and H ₂ O. The organic phase was washed with brine, dried over magnesium sulfate and evaporated to dryness. The crude product was purified by silica gel chromatography using 10-50% EtOAc in hexanes as eluent to give the desired compound (400 mg, 70%). LC/MS: 291.0 [M+H] ⁺ .

Step 6: tert-Butyl 6-(4-((((1,3-trans)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoi) Preparation of soindolin-5-yl)oxy)cyclobutyl)amino)methyl)piperidin-1-yl)nicotinate

tert-Butyl 6-(4-formylpiperidin-1-yl)nicotinate (50 mg, 0.17 mmol), 5-((1,3-trans) in DCM (10 mL) stirred at room temperature under nitrogen )-3-aminocyclobutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (58.36 mg, 0.17 mmol) and triethylamine (86.01 mg, 0.85 mmol) was added MgSO ₄ (204 mg, 1.7 mmol). The reaction mixture was stirred at room temperature for 2 hours. Then, sodium triacetoxyborohydride (90.07 mg, 0.43 mmol) was added dropwise at 0° C., and the reaction mixture was further stirred at room temperature for 2 hours. The reaction mixture was filtered and the filtrate was evaporated in vacuo to give the crude product. The crude product was purified by Prep-TLC eluting with CH ₂ Cl ₂ and MeOH (10/1) to afford the desired product (40 mg, 0.06 mmol, 35.3% yield) as a yellow solid. LC/MS: 617.6 [M+1] ⁺ .

Step 7: tert-Butyl 6-(4-((((1,3-trans)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoi) Preparation of soindolin-5-yl)oxy)cyclobutyl)(methyl)amino)methyl)piperidin-1-yl)nicotinate

tert-Butyl 6-(4-((((1,3-trans)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3) in HCOOH (4 mL)) Solution containing -dioxoisoindolin-5-yl)oxy)cyclobutyl)amino)methyl)piperidin-1-yl)nicotinate (40 mg, 0.06 mmol) and (HCHO) _n (2 mL) was stirred at room temperature for 3 hours. Then, NaBH ₄ (226.99 mg, 6 mmol) was added dropwise at 0°C. The reaction was stirred at room temperature for 3 hours. The reaction mixture was evaporated under vacuum to give the crude product. The residue was dissolved in DCM (150 mL), washed with water (20 mL) and evaporated in vacuo to give the crude product. The crude product was purified by Prep-TLC eluting with CH ₂ Cl ₂ and MeOH (10:1) to give the desired product (30 mg, 0.047 mmol, 79.2% yield) as a yellow solid. LC/MS: 631.6 [M+1] ⁺ .

Step 8: 6-(4-((((1,3-trans)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5) Preparation of -yl)oxy)cyclobutyl)(methyl)amino)methyl)piperidin-1-yl)nicotinic acid

tert-Butyl 6-(4-((((1,3-trans)-3-((2-(2,6-dioxopiferi) in DCM/TFA (5 mL, DCM/TFA =2:1)) Din-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(methyl)amino)methyl)piperidin-1-yl)nicotinate (30 mg, 0.05 mmol) The solution was stirred at room temperature for 1 hour. The reaction mixture was evaporated in vacuo to give the desired product (25 mg, 0.04 mmol, 91.4 % yield) as a yellow solid. LC/MS: 575.6 [M+1] ⁺ .

Step 9: N-((1,3-trans)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4- ((((1r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(methyl Preparation of )amino)methyl)piperidin-1-yl)nicotinamide (2-9)

6-(4-((((1,3-trans)-3-((2-(2,6-dioxopiperidin-3-yl)-1 in DMF (5 mL) stirred at room temperature under nitrogen) ,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(methyl)amino)methyl)piperidin-1-yl)nicotinic acid (20 mg, 0.03 mmol) and HATU (19.8 mg, 0.05 mmol) To the solution were added N,N-diisopropylethylamine (49.62 mg, 0.35 mmol) and intermediate 1-1 (11.54 mg, 0.035 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated in vacuo to give the crude product, which was purified by Prep-TLC (CH ₂ Cl ₂ / MeOH=10:1) to give the desired product (11 mg, 0.01 mmol, 28.7% yield) as a white solid. provided as LCMS m/z 852.6 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 11.13 (s, 1H), 9.11 (dd, J = 4.2, 1.7 Hz, 1H), 8.75 (d, J = 8.5 Hz, 1H), 8.66 (s, 1H), 8.31 (d, J = 8.3 Hz, 1H), 7.98 (d, J = 8.7 Hz, 1H), 7.89- 7.82 (m, 1H), 7.79- 7.73 (m, 1H), 7.68 (d, J = 9.2 Hz) , 1H), 7.30 (br s, 2H), 6.97 (d, J = 8.4 Hz, 1H), 6.90 (br s, 1H), 5.13 (dd, J = 12.8, 5.3 Hz, 1H), 4.97 (m, 1H), 4.49 (s, 1H), 4.46 (d, J = 12.4 Hz, 2H), 4.16 (d, J = 8.8 Hz, 1H), 4.05 (br m, 1H), 3.25-2.80 (m, 5H) , 2.78 -2.54 (m, 4H), 2.30-1.97 (m, 6H), 1.75 (m, 2H), 1.35-1.12 (m, 15H). HRMS calculated 852.3959 for C48H52N8O7 m/z, found 853.4297.

Example 2: N-((1,3-trans)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4 -((((1r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)( Synthesis of isopropyl)amino)methyl)piperidin-1-yl)nicotinamide (2-11)

Step 1: 2-(2,6-dioxopiperidin-3-yl)-5-((1,3-trans)-3-(isopropylamino)cyclobutoxy)isoindoline-1,3- Dion's production

5-((1,3-trans)-3-aminocyclobutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione in DCM (20 mL) (600 mg, 1.75 mmol), acetone (1016 mg, 17.5 mmol), TEA (354 mg, 3.5 mmol) and MgSO ₄ (4.2 g, 35 mmol) was stirred for 30 min at room temperature under nitrogen. Then, sodium triacetoxyborohydride (927 mg, 4.375 mmol) was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and the organic layer was washed with water, extracted with DCM (50 mL) and concentrated. The residue was purified by silica gel column chromatography (DCM:MeOH=10:1) to give the desired product (200 mg, 0.51 mmol, 29.3% yield) as a white solid. LC/MS: 385.7 [M+1] ⁺ .

Step 2: tert-Butyl 6-(4-((((1,3-trans)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoi) Preparation of soindolin-5-yl)oxy)cyclobutyl)(isopropyl)amino)methyl)piperidin-1-yl)nicotinate

2-(2,6-dioxopiperidin-3-yl)-5-((1,3-trans)-3-(isopropylamino)cyclobutoxy) in anhydrous THF (5 ml) stirred at room temperature tert-Butyl 6-(4-formylpiperidin-1-yl)pyridine-3-carboxylate (78 mg, 0.27 mmol) in a solution of isoindoline-1,3-dione (70 mg, 0.18 mmol) ), titanium tetraisopropanolate (50 mg) and AcOH (50 mg) were added, and the reaction mixture was stirred for 24 h at room temperature, followed by slow addition of Na(OAc) ₃ BH (95 mg, 0.4499 mmol) ( 0.5 eq per 0.5 hour). The reaction mixture was stirred at room temperature for 2 days. The reaction was diluted with 10 mL of MeOH, filtered and concentrated in vacuo to give the crude product, which was purified by flash column chromatography (DCM/MeOH=10:1) tert-butyl 6-(4- ((((1,3-trans)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl) (isopropyl)amino)methyl)piperidin-1-yl)nicotinate (60 mg, 50.5%) was obtained as a yellow solid. LC/MS: 659.6 [M+H] ⁺ .

Step 3: 6-(4-((((1,3-trans)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5) Preparation of -yl)oxy)cyclobutyl)(isopropyl)amino)methyl)piperidin-1-yl)nicotinic acid

tert-Butyl 6-(4-((((1,3-trans)-3-((2-(2,6-dioxopiperidine-3-) in TFA/DCM (1:3, 8 mL)) A solution of yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(isopropyl)amino)methyl)piperidin-1-yl)nicotinate (60 mg, 0.09 mmol) was Stirred at room temperature for 2 hours. The mixture was concentrated in vacuo to give the crude product (65 mg), which was used directly in the next step. LC/MS: 603.6 [M+H] ⁺ .

Step 4: N-((1,3-trans)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4- ((((1r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(iso Preparation of propyl) amino) methyl) piperidin-1-yl) nicotinamide (2-11)

6-(4-((((1,3-trans)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3) in DMF (5 mL) stirred at room temperature) -dioxoisoindolin-5-yl)oxy)cyclobutyl)(isopropyl)amino)methyl)piperidin-1-yl)NMI (17 mg, 0.2 mmol) in a solution of nicotinic acid (30 mg, 0.05 mmol) and TCFH (17 mg, 0.06 mmol) were added, followed by the addition of Intermediate 1-1 (17 mg, 0.05 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was quenched by addition of 15 mL of water and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried and concentrated in vacuo to give the crude product, which was purified by Prep-TLC (DCM/MeOH=10:1) to give the desired product (15 mg, 34.1%) got it LC/MS: 880.6 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ = 11.14 (s, 1H), 9.12 (s, 1H), 8.75 (d, J= 8.0 Hz, 1H), 8.67 (s, 1H), 8.32 (d, J= 8.0 Hz, 1H), 8.0 (d, J= 6.8 Hz, 1H), 7.87 (d, J= 6.8 Hz, 1H), 7.77 (s, 1H), 7.70 (d, J= 8.0 Hz, 1H), 7.32 (s, 2H), 6.98 (d, J= 8.0 Hz, 1H), 6.91 (d, J= 8.0 Hz, 1H), 5.18-5.05 (m, 2H), 4.58 - 4.45 (m, 3H), 4.27- 4.14 (m, 2H), 3.63-3.47 (m, 3H), 3.18 (br, 1H), 3.05 (br, 1H), 2.99-2.81 (m, 2H), 2.75 (br, 1H), 2.70-2.58 ( m, 2H), 2.29-2.13 (m, 2H), 2.15-1.75 (m, 4H), 1.47 (br, 1H), 1.31 (s, 6H), 1.24 (s, 9H), 0.99-0.75 (m, 4H). HRMS calculated 880.4272 for C50H56N8O7 m/z, found 881.4378.

Example 3: N-(1,3-trans)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4- ((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1- 1) Synthesis of nicotinamide (2-13)

Step 1: tert-Butyl 6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine- Preparation of 1-yl)methyl)piperidin-1-yl)nicotinate

[152] tert-butyl 6-(4-formylpiperidin-1-yl)nicotinate (200 mg, 0.69 mmol) in dichloromethane (10 mL), intermediate 1-2 (260 mg, 0.68 mmol) , To a solution of MgSO ₄ (820 mg, 6.8 mmol) was added Et ₃ N (140 mg, 1.36 mmol). The mixture was stirred at room temperature for 1 h. Then, sodium triacetoxyborohydride (430 mg, 2.04 mmol) was added slowly to the mixture. The mixture was stirred at room temperature overnight. The residue was concentrated in vacuo. The crude product was purified by silica gel chromatography using 5-10% MeOH in DCM as eluent to give the desired compound (250 mg, 59%). LC/MS: 617.3 [M+H] ⁺ .

Step 2: 6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl) Preparation of methyl)piperidin-1-yl)nicotinic acid

[153] tert-Butyl 6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline- in dichloromethane (10 mL)) To a solution of 5-yl)piperazin-1-yl)methyl)piperidin-1-yl)nicotinate (230 mg, 0.37 mmol) was added TFA (2 mL). The mixture was stirred at room temperature overnight. The residue was concentrated in vacuo. The crude product was used in the next step without further purification. LC/MS: 561.1 [M+H] ⁺ .

Step 3: N-(1,3-trans)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-( (4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl ) Preparation of nicotinamide (2-13)

[154] 6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl) pipette in DMF (7 mL)) Razin-1-yl)methyl)piperidin-1-yl)nicotinic acid (130 mg, crude), Intermediate 1-1 (92 mg, 0.28 mmol), HATU (105 mg, 0.27 mmol) and DIEA (259 mg, 2.06 mmol) was stirred at room temperature overnight. TLC showed the reaction was complete. The mixture was partitioned between EA and H ₂ O. The organic phase was washed with brine, dried over magnesium sulfate and evaporated to dryness. The crude product was purified by preparative TLC (MeOH : DCM = 1:20) to give the desired compound (60 mg, 31%). LC/MS: 838.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO) δ 11.10 (s, 1H), 9.12 (dd, J = 4.2, 1.7 Hz, 1H), 8.75 (dd, J = 8.5, 1.5 Hz, 1H), 8.65 (d, J) = 2.3 Hz, 1H), 8.31 (d, J = 8.2 Hz, 1H), 7.96 (dd, J = 9.0, 2.4 Hz, 1H), 7.77 (dd, J = 8.5, 4.3 Hz, 1H), 7.68 (dd , J = 12.2, 8.9 Hz, 2H), 7.36 (s, 1H), 7.27 (d, J = 8.7 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 6.87 (d, J = 9.1 Hz) , 1H), 5.08 (dd, J = 12.9, 5.3 Hz, 1H), 4.49 - 4.41 (m, 3H), 4.17 (d, J = 9.2 Hz, 1H), 3.46 (br s, 4H), 2.96 - 2.85 (m, 3H), 2.69 - 2.56 (m, 2H), 2.21 (d, J = 7.0 Hz, 2H), 2.05-2.01 (m, 1H), 1.90 - 1.80 (m, 3H), 1.31 (s, 6H) ), 1.24 (s, 6H), 1.20 - 1.10 (m, 2H), 4H overlapped with DMSO-d6 and were not assigned. HRMS calculated 837.3962 for C47H51N9O6 m/z, found 838.4035 (M+H] ⁺ .

Example 4: N-(1,3-trans)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4- ((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1- Synthesis of yl) pyrimidine-5-carboxamide (2-18)

Step 1: Preparation of tert-butyl 2-chloropyrimidine-5-carboxylate

[155] A mixture of 2-chloropyrimidine-5-carboxylic acid (2 g, 12.6 mmol), DMAP (154 mg, 1.26 mmol) and Boc ₂ O (5.5 g, 25.2 mmol) in t-BuOH (10 mL) was stirred at 50 °C overnight. TLC showed the reaction was complete. The organic phase was evaporated to dryness. The crude product was purified by silica gel chromatography (10-70% EtOAc in hexanes as eluent) to give the desired compound (800 mg, 29%). LC/MS: 215.2 [M+H] ⁺ .

Steps 2 to 6 were performed according to the same procedure as described in the preparation of 2-13. The desired compound 2-18 was obtained according to preparative TLC (MeOH : DCM =1:20). LC/MS: 839.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO) δ 11.12 (s, 1H), 10.14 (br, 1H), 9.12 (dd, J = 4.2, 1.7 Hz, 1H), 8.81 (s, 2H), 8.75 (dd, J) = 8.5, 1.7 Hz, 1H), 8.31 (d, J = 8.3 Hz, 1H), 7.83-7.75 (m, 2H), 7.52 (s, 1H), 7.38 (d, J = 8.2 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 5.11 (dd, J = 12.9, 5.2 Hz, 1H), 4.77 (d, J = 13.0 Hz, 2H), 4.48 (s, 1H), 4.23 (d, J = 12.0 Hz, 2H), 4.16 (d, J = 8.7 Hz, 1H), 3.63 (d, J = 11.1 Hz, 2H), 3.47 (t, J = 12.8 Hz, 2H), 3.22-3.00 (m, 4H) , 2.94-2.86 (m, 1H), 2.69-2.54 (m, 2H), 2.35-2.18 (m, 2H), 2.07-1.80 (m, 4H), 1.30 (s, 6H), 1.24 (s, 6H) , 1.23-1.10 (m, 2H); NRMS calculated 838.3915 for C46H50N10O6 m/z, found 839.4017 [M+H] ⁺ .

Example 5: N-(1,3-trans)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4- ((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1- Synthesis of yl) pyridazine-3-carboxamide (2-19)

[156] This compound was prepared using the same procedure as described for 2-13, except that tert-butyl 6-chloropyridazine-3-carboxylate was used. LC/MS: 838.7 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO) δ 11.10 (s, 1H), 9.12 (dd, J = 4.2, 1.7 Hz, 1H), 8.77 (dd, J = 8.5, 1.6 Hz, 1H), 8.31 (dd, J) = 8.7, 3.2 Hz, 2H), 7.84 (d, J = 9.6 Hz, 1H), 7.77 (dd, J = 8.5, 4.3 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.41-7.34 (m, 2H), 7.28 (d, J = 8.6 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 5.08 (dd, J = 12.9, 5.4 Hz, 1H), 4.62 (s, 1H) , 4.52 (d, J = 13.0 Hz, 2H), 4.13 (d, J = 9.1 Hz, 1H), 3.46 (br s, 4H), 3.06 (t, J = 12.1 Hz, 2H), 2.88 (dd, J) = 21.5, 9.8 Hz, 1H), 2.69-2.54 (m, 2H), 2.23 (d, J = 6.9 Hz, 2H), 2.07-1.82 (m, 4H), 1.31 (s, 6H), 1.25 (s, 6H), 1.25-1.10 (m, 2H). 4H overlapped with DMSO-d6 and was unassigned. HRMS calculated 838.3915 for C46H50N10O6 m/z, found 839.4018 [M+H] ⁺ .

Example 6: N-(1,3-trans)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4- ((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1- 1) Synthesis of benzamide (2-21)

[157] This compound was prepared using the same method as described for the preparation of 2-13 except that tert-butyl 4-fluorobenzoate was used. LC/MS: 837.4 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO) δ 11.10 (s, 1H), 9.11 (dd, J = 4.2, 1.6 Hz, 1H), 8.74 (dd, J = 8.5, 1.6 Hz, 1H), 8.31 (d, J) = 8.3 Hz, 1H), 7.80-7.73 (m, 3H), 7.69 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.35 (s, 1H), 7.27 (d) , J = 8.0 Hz, 1H), 7.00-6.95 (m, 3H), 5.08 (dd, J = 5.2, 12.4 Hz, 1H), 4.50 (s, 1H), 4.16 (d, J = 8.7 Hz, 1H) , 3.87 (br d, J = 12.4 Hz, 2H), 3.47-3.42 (m, 4H), 2.95-2.73 (m, 3H), 2.62-2.53 (m, 2H), 2.50 (m, 4H), 2.21 ( br d, J = 6.4 Hz, 2H), 2.07-1.98 (m, 1H), 1.85-1.71 (m, 3H), 1.30 (s, 6H), 1.24 (s, 6H), 1.24-1.11 (m, 2H) ); HRMS calculated 836.4010 for C48H52N8O6 m/z, found 837.4094 [M+H] ⁺ .

Example 7: N-(1,3-trans)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4- ((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1- Synthesis of yl)-3-fluorobenzamide (2-22)

[158] This compound was prepared using methods analogous to those described for the synthesis of 2-13. The crude product was purified by preparative HPLC to give the title compound (33 mg, 23%). LC/MS: 854.5 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO) δ 11.11 (s, 1H), 9.12 (d, J = 3.1 Hz, 1H), 8.75 (d, J = 8.1 Hz, 1H), 8.32 (d, J = 8.2 Hz, 1H), 7.83-7.75 (m, 3H), 7.75 - 7.61 (m, 2H), 7.53-7.27 (m, 2H), 7.12 (t, J = 8.5 Hz, 1H), 6.98 (d, J = 8.3 Hz) , 1H), 5.10 (dd, J = 12.6, 5.0 Hz, 1H), 4.51 (s, 1H), 4.18 (d, J = 8.1 Hz, 1H), 3.62-3.40 (m, 6H), 3.12 (br, 2H), 2.96 - 2.87 (m, 1H), 2.79 (t, J = 11.2 Hz, 2H), 2.66 - 2.55 (m, 2H), 2.14 - 1.71 (m, 4H), 1.31 (s, 6H), 1.25 (s, 6H), 1.25-1.10 (m, 2H). 4H overlapped with DMSO-d6 and was unassigned.

Example 8: N-(1,3-trans)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4- ((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1 Synthesis of -yl)-3-fluorobenzamide (2-32)

Step 1: tert-Butyl (S)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazine Preparation of -1-yl)methyl)piperidin-1-yl)-3-fluorobenzoate

[159] tert-butyl 3-fluoro-4-(4-formylpiperidin-1-yl)benzoate (31 mg, 0.1 mmol) and Intermediate 1 in DCM (2 mL) stirred at room temperature under nitrogen To a solution of -4 (48.6 mg, 0.1 mmol) was added magnesium sulfate (240 mg, 2 mmol) and triethylamine (20 mg, 0.2 mmol). The reaction mixture was stirred at room temperature for 1 hour. Then NaBH(OAc) ₃ (53 mg, 0.25 mmol) was added in portions. The reaction was stirred for 1 hour. The solvent was removed in vacuo to give the crude product, which was purified by silica gel column chromatography (eluted with 0-15% MeOH in DCM) to give the title compound (60 mg, 96%). LC/MS: 619.8 [M+H] ⁺ .

Step 2: (S)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl Preparation of )methyl)piperidin-1-yl)-3-fluorobenzoic acid

[160] (S)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl) in DCM (2 mL)) To a solution of piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorobenzoate (60 mg, 0.09 mmol) was added TFA (0.4 mL). The reaction was stirred overnight. The solvent was removed in vacuo to give the crude product (55 mg, 100%). LC/MS:563.7 [M+H] ⁺ .

Step 3: N-(1,3-trans)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-( (4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1- Preparation of yl)-3-fluorobenzamide (2-32)

[161] (S)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoin) in DMF (2 mL) stirred at room temperature under nitrogen A solution of dolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorobenzoic acid (55 mg, 0.09 mmol) and intermediate 1-1 (34 mg, 0.1 mmol) To this was added HATU (57 mg, 0.15 mmol) and DIEA (39 mg, 0.3 mmol). The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo to give the crude product, which was further purified by flash column chromatography to N-(1,3-trans)-3-((8-cyanoquinolin-5-yl)oxy)- 2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline) 5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorobenzamide was obtained as a solid (39 mg, 51%). LC/MS: 841.5 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 9.12 (dd, J = 4.2, 1.7 Hz, 1H), 8.75 (dd, J = 8.5, 1.6 Hz, 1H), 8.32 (d, J ) = 8.3 Hz, 1H), 7.83 - 7.73 (m, 2H), 7.72 - 7.62 (m, 2H), 7.54 (d, J = 8.1 Hz, 1H), 7.15 - 7.03 (m, 3H), 6.97 (d, J = 8.4 Hz, 1H), 5.06 (dd, J = 13.2, 5.0 Hz, 1H), 4.50 (s, 1H), 4.34 (d, J = 16.8 Hz, 1H), 4.22 (d, J = 16.8 Hz, 1H), 4.17 (d, J = 8.8 Hz, 1H), 3.50 (br d, J = 11.7 Hz, 2H), 3.30 (m, 4H), 2.98 - 2.87 (m, 1H), 2.76 (t, J = 11.2 Hz, 2H), 2.65 - 2.53 (m, 5H), 2.45 - 2.30 (m, 1H), 2.26 (br d, J = 6.8 Hz, 2H), 2.02 - 1.93 (m, 1H), 1.90 - 1.80 ( m, 2H), 1.80 - 1.70 (brs, 1H), 1.31 (s and m, 7H), 1.24 (s and m, 7H); HRMS calculated 840.4123 for C48H53FN8O5 m/z, found 841.4221 [M+H] ⁺ .

Example 9: N-(1,3-trans)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4- ((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1 -yl) nicotinamide 2-29) synthesis

[162] Compound 2-29 was prepared using a method similar to that for the preparation of 2-32. LC/MS: 823.7 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 9.12 (dd, J = 4.0, 2.0 Hz, 1H), 8.75 (dd, J = 8.5, 1.6 Hz, 1H), 8.66 (s, 1H) ), 8.32 (d, J = 8.3 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.76 (m, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.54 (d, J) = 8.0 Hz, 1H), 7.14-7.03 (m, 2H), 6.98 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 5.07 (dd, J = 13.0, 5.0 Hz) , 1H), 4.49 (s, 1H), 4.43 (br d, J = 11.7 Hz, 2H), 4.34 (d, J = 16.8 Hz, 1H), 4.22 (d, J = 16.8 Hz, 1H), 4.17 ( d, J = 8.7 Hz, 1H), 3.30 (br s, 4H), 2.98-2.80 (m, 3H), 2.70-2.50 (m, 4H), 2.45 - 2.30 (m, 2H), 2.20 (br d, 2H), 2.01 - 1.78 (m, 4H), 1.31 (s, 6H), 1.24 (s, 6H), 1.24-1.03 (m, 2H); HRMS calculated 823.4170 for C47H53N9O5 m/z, found 824.4475 [M+H] ⁺ .

Example 10: N-(1,3-trans)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4- ((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1 -yl) pyrimidine-5-carboxamide 2-30) synthesis

Compounds 2-30 were prepared using the same method as for the preparation of 2-32. LC/MS: 824.5 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 9.12 (s, 1H), 8.83 (s, 1H), 8.75 (dd, J = 8.4 Hz, 1H), 8.31 (d, J = 8.5 Hz, 1H), 7.93 (m, 1H), 7.76 (m, 1H), 7.68-7.45 (m, 2H), 7.23-7.05 (m, 2H), 6.98 (d, J = 8.4 Hz, 1H), 5.07 (m, 1H), 4.76 (br d, J = 12.0 Hz, 2H), 4.52 (s, 1H), 4.36 (d, J = 16.8 Hz, 1H), 4.23 (d, J = 16.8 Hz, 1H), 4.16 (d, J = 8.6 Hz, 1H), 3.30-3.26 (m, 4H), 3.15-2.80 (m, 3H), 2.70-2.54 (m, 2H), 2.47-2.30 (m, 4H), 2.22 ( m, 2H), 2.05-1.75 (m, 4H), 1.35-1.05 (m, 14H). HRMS calculated 824.4122 for C46H52N10O5 m/z, found 825.4199 [M+1] ⁺ .

Example 11: N-((1,3-trans)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4 -((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin- Synthesis of 1-yl) pyridazine-3-carboxamide (2-31)

Compound 2-31 was prepared using methods analogous to those for the preparation of 2-32. LC/MS: 825.5 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO) δ 10.96 (s, 1H), 9.11 (dd, J = 4.2, 1.5 Hz, 1H), 8.76 (d, J = 8.5 Hz, 1H), 8.35 - 8.27 (m, 2H) ), 7.85 (d, J = 9.5 Hz, 1H), 7.79 - 7.75 (m, 1H), 7.58 - 7.50 (m, 1H), 7.42-7.35 m, 1H), 7.17- 7.03 (m, 2H), 7.01 (d, J = 8.4 Hz, 1H), 5.06 (dd, J = 13.2, 4.8 Hz, 1H), 4.61 (s, 1H), 4.52 (d, J = 13.0 Hz, 2H), 4.34 (d, J = 17.0 Hz, 1H), 4.22 (d, J = 17.1 Hz, 1H), 4.14 (d, J = 9.1 Hz, 1H), 3.30 - 3.26 (m, 4H), 3.20 -3.03 (m, 2H), 2.96 - 2.84 (m, 1H), 2.68 - 2.53 (m, 5H), 2.43 - 2.32 (m, 1H), 2.22 (m, 2H), 2.02 - 1.78 (m, 4H), 1.32 - 1.08 (m, 14H); HRMS calculated 824.4122 for C46H52N10O5 m/z, found 825,4214 [M+H] ⁺ .

Example 12: N-((1,3-trans)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4 -((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl) Synthesis of piperidin-1-yl)pyridazine-3-carboxamide (2-35)

Compounds 2-35 were prepared using methods analogous to those for the preparations of 2-32, and intermediates 1-5 were used in the reductive amination step. LC/MS: 856.4 [M+1] ⁺ ; ¹ H NMR (400 MHz, DMSO) δ 11.12 (s, 1H), 9.11 (dd, J = 4.2, 1.6 Hz, 1H), 8.76 (dd, J = 8.5, 1.5 Hz, 1H), 8.31 (dd, J) = 8.7, 3.4 Hz, 2H), 7.84 (d, J = 9.6 Hz, 1H), 7.79- 7.72 (m, 2H), 7.47 (d, J = 6.8 Hz, 1H), 7.38 (d, J = 9.5 Hz) , 1H), 7.01 (d, J = 8.4 Hz, 1H), 5.12 (dd, J = 12.8, 5.3 Hz, 1H), 4.61 (s, 1H), 4.52 (d, J = 12.8 Hz, 2H), 4.12 (d, J = 9.1 Hz, 1H), 3.27 (br s, 4H), 3.05 (t, J = 11.9 Hz, 2H), 2.89- 2.55 (m, 1H), 2.70 - 2.52 (m, 6H), 2.28 -2.20 (m, 2H), 2.11 - 2.01 (m, 1H), 1.99 - 1.75 (m, 3H), 1.31 (s, 6H), 1.23 (s, 6H), 1.19-1.13 (m, 2H). HRMS calculated 856.3821 for C46H49FN10O6 m/z, found 857.3925.

Example 13: N-((1,3-trans)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4 -((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl) Synthesis of piperidin-1-yl)nicotinamide 2-36)

Compounds 2-36 were prepared using methods analogous to those for the preparations of 2-32, and intermediates 1-5 were used in the reductive amination step. LC/MS: 855.5 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO) δ 11.13 (s, 1H), 9.12 (dd, J = 4.4, 1.7 Hz, 1H), 8.75 (dd, J = 8.4, 1.7 Hz, 1H), 8.66 (s, 1H) ), 8.32 (d, J = 8.4 Hz, 1H), 7.99 (m, 1H), 7.85 - 7.69 (m, 3H), 7.47 (d, J = 8.7 Hz, 1H), 6.99 (d, J = 8.8 Hz) , 1H), 6.87 (m, 1H), 5.16 - 5.09 (m, 1H), 4.51 (s, 1H), 4.44 (d, J = 12.0 Hz, 2H), 4.17 (d, J = 9.2 Hz, 1H) , 3.84 - 3.58 (m, 2H), 3.27 (br s, 4H), 3.00 - 2.83 (m, 3H), 2.75 - 2.50 (m, 4H), 2.22 (br d, 2H), 2.11-1.95 (m, 2H), 1.90 - 1.77 (m, 2H), 1.31 (s, 6H), 1.24 (s, 6H), 1.24-1.05 (m, 2H). HRMS calculated 855.3868 for C47H50FN9O6 m/z, found 856.3931 [M+1] ⁺ .

Example 14: N-(1,3-trans)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4- (2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin- Synthesis of 1-yl)benzamide (2-43)

Step 1: Preparation of tert-butyl 4-(4-(2-hydroxyethyl)piperidin-1-yl)benzoate

[163] tert-butyl 4-fluorobenzoate (200 mg 1.02 mmol), 2-(piperidin-4-yl)ethanol (131.6 mg 1.02 mmol), potassium carbonate (422.6 mg) in DMF (5 mL) 3.06 mmol) was stirred at 100° C. under nitrogen for 18 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH: dichloromethane = 1:10) to give the target compound (210 mg, 0.69 mmol, 67% yield) as a white solid. LC/MS: 306 [M+H] ⁺ .

Step 2: Preparation of tert-butyl 4-(4-(2-oxoethyl)piperidin-1-yl)benzoate

[164] tert-Butyl 4-[4-(2-hydroxyethyl)piperidin-1-yl]benzoate (200 mg, 0.69 mmol) and IBX (218.42 mg 0.78 mmol) in DMSO (4 mL) The mixture was stirred at 50 °C under nitrogen for 18 hours. The reaction mixture was treated with 20 mL of water and extracted with EtOAc (3×5 mL). The combined organic phases were washed with water (5 mL), dried over MgSO ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (EA: dichloromethane = 1:5) to give the target compound (150 mg, 0.49 mmol, 72% yield) as a gray solid. LC/MS: 304.0 [M+H] ⁺ .

Step 3: tert-Butyl 4-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pipeline) Preparation of Razin-1-yl)ethyl)piperidin-1-yl)benzoate

[165] tert-Butyl 4-[4-(2-oxoethyl)piperidin-1-yl]benzoate (150 mg, 0.49 mmol), DIPEA (63.9 mg, 0.49 mmol) in dichloromethane (3 mL) ), intermediate 1-2 (187.4 mg, 0.49 mmol) and MgSO ₄ (300 mg) was added NaHB(OAc) ₃ (314.4 mg, 1.48 mmol). The mixture was stirred at 25° C. for 18 h. The residue was diluted with water (50 mL) and extracted with dichloromethane (50 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to afford the desired compound as a yellow solid (240 mg, 0.38 mmol, 78% yield). LC/MS: 630.3 [M+H] ⁺ .

Step 4: 4-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1- Preparation of yl) ethyl) piperidin-1-yl) benzoic acid

[166] tert-butyl 4-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1 in DCM (5 mL) and TFA (0.5 mL)), A mixture of 3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)benzoate (240 mg, 0.38 mmol) was stirred at 25° C. for 18 hours. The reaction mixture was concentrated under reduced pressure to give the target compound (220 mg, 0.38 mmol, 100% yield) as a yellow solid. LC/MS: 574.2 [M+H] ⁺ .

Step 5: N-(1,3-trans)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-( 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1 Preparation of -yl) benzamide (2-43)

[167] 4-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl) in DMF (5 mL) In a mixture of )piperazin-1-yl)ethyl)piperidin-1-yl)benzoic acid (100 mg, 0.17 mmol), intermediate 1-1 (56.44 mg, 0.17 mmol) and DIEA (87.88 mg, 0.68 mmol) HATU (84.03 mg, 0.22 mmol) was added dropwise. The resulting mixture was stirred at 25° C. for 18 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH ₃ :MeOH:dichloromethane = 1:10:100) to give the target compound (50 mg, 0.06 mmol, 35% yield) as a brown solid. LC/MS: 852.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO) δ 11.10 (s, 1H), 9.12 (dd, J = 4.2, 1.7 Hz, 1H), 8.75 (dd, J = 8.5, 1.7 Hz, 1H), 8.32 (d, J) = 8.2 Hz, 1H), 8.20 (br, 1H), 7.76 (m, 2H), 7.69 (m, 1H), 7.57 (d, J = 9.2 Hz, 1H), 7.36 (m, 1H), 7.28 (m) , 1H), 6.97 (m, 3H), 5.09 (dd, J = 12.8, 5.3 Hz, 1H), 4.50 (s, 1H), 4.17 (d, J = 9.2 Hz, 1H), 3.87 (d, J = 12.6 Hz, 2H), 3.71-3.54 (m, 2H), 3.52-3.38 (m, 2H), 3.15 (td, J = 11.6, 7.4 Hz, 2H), 2.96-2.83 (m, 1H), 2.78 (t) , J = 11.5 Hz, 2H), 2.68-2.53 (m, 4H), 2.45-2.29 (m, 2H), 2.10 - 1.94 (m, 1H), 1.78 (br d, J = 12.5 Hz, 2H), 1.59 -1.38 (m, 3H), 1.32 - 1.10 (m, 14H). HRMS calculated 850.4166 for C49H54N8O6 m/z, found 851.4273 [M+H] ⁺ .

Example 15: N-((1,3-trans)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4 -((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl) Synthesis of piperidin-1-yl)benzamide (2-47)

Compound 2-47 was prepared using methods analogous to those for the preparation of 2-32, and intermediates 1-5 were used in the reductive amination step. LC/MS: 854.4 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 11.14 (s, 1H), 9.13 (s, 1H), 8.76 (d, J = 8.4 Hz, 1H), 8.32 (d, J = 8.3 Hz, 1H), 7.85- 7.72 (m, 4H), 7.68 - 7.29 (m, 2H), 6.99 (m, 3H), 5.13 (d, J = 12.1 Hz, 1H), 4.51 (s, 1H), 4.18 (d, J = 8.6 Hz) , 1H), 3.89 (d, J = 10.7 Hz, 2H), 3.28 (br s, 4H), 2.99-2.75 (3H), 2.72- 2.50 (m, 6H), 2.24 (br, 2H), 2.07 (m) , 1H), 1.89-1.75 (m, 3H), 1.31 (s, 6H), 1.25 (s, 6H), 1.25-1.10 (m, 2H). C48H51FN8O6 calculated 854.3916 for m/z, found 855.4013 [M+H] ⁺ .

Example 16: N-((1,3-trans))-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-( 4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl ) Synthesis of piperidin-1-yl)-3-fluorobenzamide (2-48)

Compound 2-48 was prepared using methods analogous to those for the preparation of 2-32, and intermediates 1-5 were used in the reductive amination step. LC/MS: 872.5 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO) δ 11.12 (s, 1H), 9.11 (dd, J = 4.2, 1.6 Hz, 1H), 8.75 (d, J = 8.5 Hz, 1H), 8.31 (d, J = 8.3) Hz, 1H), 7.76 (m, 3H), 7.69-7.64 (m, 2H), 7.46 (d, J = 7.3 Hz, 1H), 7.10 (t, J = 8.7 Hz, 1H), 6.97 (d, J ) = 8.4 Hz, 1H), 5.11 (dd, J = 12.8, 5.2 Hz, 1H), 4.50 (s, 1H), 4.17 (d, J = 9.1 Hz, 1H), 3.50 (d, J = 11.5 Hz, 2H) ), 3.28 (br s, 4H), 2.95-2.82 (m, 1H), 2.75 (m, 2H), 2.68 - 2.51 (m, 6H), 2.22 (br d, 2H), 2.07 - 2.00 (m, 1H) ), 1.92-1.78 (m, 2H), 1.75 (s, 1H), 1.30 (s and m, 7H), 1.24 (s and m, 7H). HRMS calculated 872.3821 for C48H50F2N8O6 m/z, found 873.3906 [M+H] ⁺ .

Example 17: N-((1,3-trans)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4 -((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin- Synthesis of 1-yl)benzamide 2-49)

Compound 2-49 was prepared using the same method as for the preparation of 2-32. The final compound was purified as TSA salt by HPLC. LC/MS: 823.5 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 9.17 - 9.07 (m, 1H), 8.79 - 8.70 (m, 1H), 8.32 (d, J = 8.3 Hz, 1H), 7.80 - 7.75 (m, 4H), 7.66 - 7.47 (m, 2H), 7.17 - 6.91 (m, 4H), 5.12 - 5.00 (m, 1H), 4.50 (s, 1H), 4.32 (d, J = 16.8 Hz, 1H) ), 4.28 - 4.08 (m, 2H), 3.99 - 3.81 (m, 2H), 3.69 - 3.54 (m, 1H), 3.32 (br s, 4H), 3.19-3.10 (m, 1H), 3.01 - 2.74 ( m, 3H), 2.70 - 2.50 (m, 3H), 2.42 - 2.34 (m, 1H), 2.32 - 2.11 (m, 2H), 2.04 - 1.94 (m, 1H), 1.94 - 1.66 (m, 3H), 1.32 - 1.21 (m, 14H). HRMS calculated 822.4217 for C48H54N8O5 m/z, found 823.4302 [M+1] ⁺ .

Example 18: N-((1,3-trans)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4 -((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl) Synthesis of piperidin-1-yl)pyrimidine-5-carboxamide (2-50)

Compounds 2-50 were prepared using methods analogous to those for the preparations of 2-32, and intermediates 1-5 were used in the reductive amination step. LC/MS: 856.6 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO) δ 11.13 (s, 1H), 9.11 (d, J = 2.8 Hz, 1H), 8.92 - 8.68 (m, 3H), 8.31 (d, J = 8.2 Hz, 1H), 7.96 - 7.69 (m, 3H), 7.48 (br s, 1H), 6.98 (d, J = 8.3 Hz, 1H), 5.12 (dd, J = 12.6, 5.0 Hz, 1H), 4.77 (d, J = 12.7) Hz, 2H), 4.47 (s, 1H), 4.15 (d, J = 9.1 Hz, 1H), 3.28 (br s, 4H), 3.17 - 2.74 (m, 4H), 2.67-2.53 (m, 5H), 2.22 (br s, 2H), 2.11-1.99 (m, 1H), 1.92-1.79 (m, 3H), 1.31 (s, 6H), 1.24 (s, 6H), 1.16-1.02 (m, 2H). HRMS calculated 856.3821 for C46H49FN10O6 m/z, found 857.3902 [M+H] ⁺ .

Example 19: N-((1,3-trans)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4 -((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl) Synthesis of piperidin-1-yl)-5-fluoronicotinamide (2-52)

Compound 2-52 was prepared using methods analogous to those for the preparation of 2-32. LC/MS: 873.6 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO) δ 11.13 (s, 1H), 9.12 (dd, J = 4.2, 1.7 Hz, 1H), 8.75 (dd, J = 8.5, 1.7 Hz, 1H), 8.53 (s, 1H) ), 8.31 (d, J = 8.8 Hz, 1H), 7.91 (d, J = 15.0 Hz, 1H), 7.83 - 7.73 (m, 3H), 7.47 (d, J = 7.1 Hz, 1H), 6.98 (d) , J = 8.4 Hz, 1H), 5.12 (dd, J = 12.6, 5.4 Hz, 1H), 4.49 (s, 1H), 4.27 - 4.16 (m, 3H), 3.27 (br s, 4H), 3.04 - 2.84 (m, 3H), 2.69-2.52 (m, 6H), 2.23 (br d, 2H), 2.06 - 2.02 (m, 1H), 1.90-1.75 (m, 3H), 1.31 (s, 6H), 1.24 ( s, 6H), 1.24-1.18 (m, 2H). HRMS calculated 873.3774 for C47H49F2N9O6 m/z, found 874.4107 [M+H] ⁺ .

Example 20: N-((1,3-trans)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4 -((4-(2-((S)-2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl ) Synthesis of piperidin-1-yl)-3-fluorobenzamide (2-53)

Step 1: tert-Butyl (S)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindoline-5) Preparation of -yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorobenzoate

Intermediate 1- To a solution of tert-butyl 3-fluoro-4-(4-formylpiperidin-1-yl)benzoate (100 mg, 0.33 mmol) in DCM (20 mL) stirred at room temperature under argon 3 (166.5 mg, 0.33 mmol), MgSO ₄ (396 mg, 3.3 mmol) and TEA (200 mg, 1.98 mmol) were added. The reaction mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added sodium triacetoxyborohydride (175 mg, 0.825 mmol). The reaction mixture was stirred at room temperature for 2 hours. The solution was filtered and the filtrate was concentrated. The residue was purified by Prep-TLC (DCM/MeOH=20:1) and tert-butyl (S)-4-(4-((4-(2-(2,6-dioxopiperidine-3) -yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorobenzoate (100 mg, 47.5%) got LC/MS: 637.6 [M+H] ⁺ .

Step 2: (S)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)pipe Preparation of Razin-1-yl)methyl)piperidin-1-yl)-3-fluorobenzoic acid

tert-Butyl (S)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-) in DCM (5 mL) stirred at room temperature To a solution of 1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorobenzoate (100 mg, 0.157 mmol) was added TFA (3 mL) added. The reaction mixture was stirred at room temperature for 2 hours. The crude product was concentrated in vacuo and used directly in the next step. LC/MS: 581.7 [M+H] ⁺ .

Step 3: N-((1,3-trans)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4- ((4-(2-((S)-2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl) Preparation of piperidin-1-yl)-3-fluorobenzamide (2-53)

(S)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-yl) in DMF (5 mL) stirred at room temperature under argon HATU (97 mg, 0.255 mmol) in a solution of oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorobenzoic acid (100 mg, 0.17 mmol), Intermediate 1-1 (56.4 mg, 0.17 mmol) and DIEA (132 mg, 1.02 mmol) were added. The reaction mixture was stirred at room temperature overnight. The crude product was concentrated in vacuo. The residue was extracted with DCM (3×20 mL) and purified by Prep-TLC (DCM/MeOH=10:1) to give the title compound as a white solid (59 mg, 38.9%). LC/MS: 858.6 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 9.11 (dd, J = 4.4, 1.7 Hz, 1H), 8.75 (dd, J = 8.4, 1.7 Hz, 1H), 8.31 (d, J) = 8.4 Hz, 1H), 7.81 - 7.64 (m, 4H), 7.47-7.35 (m, 1H), 7.30-7.18 (m, 1H), 7.15-7.05 (m, 1H), 6.97 (d, J = 8.4 Hz, 1H), 5.15-5.05 (m, 1H), 4.50 (s, 1H), 4.38 (d, J = 16.4 Hz, 1H), 4.25 (d, J = 16.4 Hz, 1H), 4.17 (d, J) = 9.2 Hz, 1H), 3.70-3.55 (m, 2H), 3.55-3.45 (m, 2H), 3.32 - 3.24 (m, 1H), 3.14 (br s, 3H), 2.95 - 2.87 (m, 1H) , 2.81-2.71 (m, 2H), 2.65-2.55 (m, 3H), 2.47-2.30 (m, 1H), 2.26 (br d, 2H), 2.10-1.95 (m, 2H), 1.90-1.75 (m , 2H), 1.31 (s, 7H), 1.24 (s, 7H). HRMS calculated 858.4029 for C48H52F2N8O5 m/z, found 859.4251 [M+H] ⁺ .

[168] Testing of compounds for AR degrading activity

[169] LNCAP, VCAP and 22Rv1 cells were plated in 24-well plates at 1.5×10E5 cells/well in RPMI growth medium containing 10% FBS and 1% penicillin streptomycin, followed by incubation at 37° C. overnight. The next day, test compounds were administered to the cells using 1000x compound stock solutions prepared in various concentrations of DMSO. After compound administration, cells were then incubated at 37° C. for 24 hours. Upon completion, cells were washed with PBS and proteins were collected in Laemmli sample buffer (1x; VWR International). Proteins from cell lysates were separated by SDS-PAGE and transferred to Odyssey nitrocellulose membranes (Licor) using an iblot® dry blotting transfer system (ThermoFisher). The membrane was incubated with Intercept Blocking Buffer (Licor) at room temperature for 1 hour with gentle shaking to block non-specific binding. Then, primary antibodies rabbit anti-AR (1:1,000, Cell Signaling, 5153) and mouse anti-GAPDH (1:5,000, Santa Cruz Biotechnology, sc-47724) diluted with Intercept Blocking Buffer containing 0.1% Tween 20 were combined with Together, the membranes were incubated overnight at 4°C. After washing three times with TBS-T, the membranes were incubated with either IRDye® 800CW goat anti-mouse IgG (1:20,000, Licor) or IRDye® 800CW goat anti-rabbit IgG (1:20,000, Licor) for 1 hour. After TBS-T wash, the membrane was rinsed with TBS and scanned with an Odyssey® CLx imaging system (Licor). Bands were quantified using Image Studio™ Software (Licor).

[170] Inhibition of cell growth for Ramos cells

[171] RAMOS cells (ATCC) were seeded in 96 well plates at 16,000 cells/well in 90 μl RPMI growth medium containing 10% heat-inactivated fetal bovine serum and 1% penicillin/streptomycin. Test compounds were administered to cells using 10x compound stock solutions prepared in various concentrations of growth medium. After compound administration, cells were incubated at 37° C. for 3 days. Plates were equilibrated for about 10 minutes at room temperature prior to CellTiter-Glo assay. 100 ul of CellTiter-Glo® reagent (Promega) was added to each well. Plates were then incubated for 10 min at room temperature and luminescence was recorded with an EnSpire plate reader (PerkinElmer).

[172] Inhibition of cell growth on VCAP cells

[173] VCAP cells (ATCC) were seeded in 96 well plates at 3000 cells/well in 80 μl of DMEM growth medium containing 10% decharcoated FBS (CSS) and 1% penicillin/streptomycin. Cells were incubated overnight at 37°C. The next day, test compounds were administered to the cells using 10x compound stock solutions prepared in various concentrations of growth medium. After 4 hours, 0.1 nM R1881 (Sigma) was administered to the cells using a 10x compound stock solution prepared in growth medium. 0.1% DMSO with or without 0.1 nM R1881 was administered as a control. The cells were then incubated at 37° C. for 6 days. Plates were equilibrated for approximately 10 minutes at room temperature prior to CellTiter-Glo assay. 100 ul of CellTiter-Glo® reagent (Promega) was added to each well. Plates were then incubated for 10 min at room temperature and luminescence was recorded with an EnSpire plate reader (PerkinElmer).

[174] Table 4 shows (a) LNCAP, VCAP and 22Rv1 cell lines 24 hours after compound administration; (b) a RAMOS cell line 3 days after compound administration; and (c) summary of androgen receptor (AR) cleavage activity and cell growth inhibition of exemplary compounds in VCAP cell lines 6 days after compound administration. DC50: Compound concentration required for 50% target protein degradation.

Table 4: AR Degrading Activity of Compounds Obtained in Cell Assay

[175] The various features and advantages of the present disclosure are apparent from the detailed description, and it is, therefore, provided by the appended claims to include all such features and advantages of the present disclosure that fall within the true spirit and scope of the present disclosure. It is intended Moreover, it is not desired to limit the precise structure and operation of the present disclosure illustrated and described, since many modifications and variations will readily occur to those skilled in the art, and accordingly, all suitable modifications and equivalents will be incorporated into the present disclosure. may be considered to be within the scope.

[176] Those skilled in the art will also recognize that the concepts based on the present disclosure may readily be used as a basis for designing other structures, methods, and systems for carrying out the various purposes of the present disclosure. Accordingly, the claims should not be construed as limited by the above description or examples.

Claims (83)

A compound of formula (1) or a pharmaceutically acceptable salt thereof:

In the above formula:
X ₁ is CR ₁ or N;
X ₂ is CR ₂ or N;
X ₃ is CR ₃ or N;
X ₄ is CR ₄ or N;
each of R ₁ , R ₂ , R ₃ , and R ₄ is independently selected from hydrogen, halogen, C ₁ -C ₃ alkoxy, and C ₁ -C ₃ haloalkyl, each of which is 0, 1, 2, or 3 substituted with R _S ;
each R ₅ is independently selected from halogen, hydroxyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl, —N(R ₉ ) ₂ , and —CN, which are each is substituted with 0, 1, 2, or 3 R _S ;
each R ₆ is independently selected from hydrogen, halogen, C ₁ -C ₃ alkyl, and C ₁ -C ₃ haloalkyl, each of which is substituted with 0, 1, 2, or 3 R _S ; two R ₆ groups taken together form oxo;
each R ₇ is independently selected from halogen, hydroxyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl, —N(R ₉ ) ₂ , and —CN, which are each is substituted with 0, 1, 2, or 3 R _S ;
each R ₈ is independently selected from hydrogen, hydroxyl, C ₁ -C ₃ alkyl, and C ₁ -C ₃ haloalkyl, each of which is substituted with 0, 1, 2, or 3 R _S ; two R ₈ groups taken together form oxo;
each R ₉ is independently hydrogen, C ₁ -C ₃ alkyl, -C(=O)-(C ₁ -C ₃ alkyl), -C(=O)-O-(C ₁ -C ₃ alkyl), and -C(=O)-NH-(C ₁ -C ₃ alkyl), each of which is substituted with 0, 1, 2, or 3 R _S ; two R ₉ groups taken together form a 3-6 membered heterocycle or heteroaryl;
each R _s is independently selected from halogen, hydroxyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl, —N(R ₉ ) ₂ , and —CN,
L is a linker of 1 to 16 carbon atoms in length, wherein at least one carbon atom is C(O), O, N(R ₉ ), S, C ₂ -alkenyl, C ₂ -alkynyl, cycloalkyl, aryl , heterocycle, or heteroaryl, wherein R ₉ , C ₂ -alkenyl, cycloalkyl, aryl, heterocycle, and heteroaryl are each independently substituted with 0, 1, 2, or 3 R _S become;
m is 0, 1, or 2;
n is 0, 1, 2, or 3;
o is 0, 1, 2, or 3;
wherein each hydrogen atom is independently and optionally replaced by a deuterium atom. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein X ₁ is N. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein X ₂ is N. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein X ₁ and X ₂ are each N. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein X ₂ is CR ₂ , X ₃ is CR ₃ , and X ₄ is CR ₄ . The compound or a pharmaceutically acceptable salt thereof according to claim 5, wherein R ₂ , R ₃ , and R ₄ are each independently selected from H and F. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein X ₁ is CR ₁ , X ₂ is CR ₂ , X ₃ is CR ₃ , and X ₄ is CR ₄ . The compound or a pharmaceutically acceptable salt thereof according to claim 7, wherein R ₁ , R ₂ , R ₃ , and R ₄ are each independently selected from H and F. The compound or a pharmaceutically acceptable salt thereof according to claim 7 or 8, wherein R ₁ is F. The compound or a pharmaceutically acceptable salt thereof according to claim 7 or 8, wherein R ₂ is F. The compound or a pharmaceutically acceptable salt thereof according to claim 7 or 8, wherein R ₃ is F. The compound or a pharmaceutically acceptable salt thereof according to claim 7 or 8, wherein R ₄ is F. The compound or a pharmaceutically acceptable salt thereof according to claim 7 or 8, wherein R ₁ and R ₃ are each F. The compound or a pharmaceutically acceptable salt thereof according to claim 7 or 8, wherein R ₃ and R ₄ are each F. 10. The compound or pharmaceutically acceptable salt thereof according to claim 9, wherein R ₂ , R ₃ , and R ₄ are each H. 11. The compound or pharmaceutically acceptable salt thereof according to claim 10, wherein R ₁ , R ₃ , and R ₄ are each H. 12. The compound or pharmaceutically acceptable salt thereof according to claim 11, wherein R ₁ , R ₂ , and R ₄ are each H. 13. The compound or pharmaceutically acceptable salt thereof according to claim 12, wherein R ₁ , R ₂ , and R ₃ are each H. 14. The compound or pharmaceutically acceptable salt thereof according to claim 13, wherein R ₂ and R ₄ are each H. 15. The compound or pharmaceutically acceptable salt thereof according to claim 14, wherein R ₁ and R ₂ are each H. The method of claim 1,

giga

A compound selected from, or a pharmaceutically acceptable salt thereof. 22. The compound of any one of claims 1-21, wherein each R ₅ is independently selected from halogen, C ₁ -C ₃ alkoxy, and C ₁ -C ₃ haloalkyl. salt. 23. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-22, wherein each R ₅ is independently selected from -Cl, -OCH ₃ , and -CF ₃ . 24. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 23, wherein m is 0 or 1. 25. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 24, wherein m is 0. 26. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 25, wherein m is 1. 27. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 26, wherein o is 0. 27. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-26, wherein o is 1. 24. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 23, wherein m and o are each 0. 30. The compound of any one of claims 1-29, wherein each R ₆ is independently selected from H and C ₁ -C ₃ alkyl. 31. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 30, wherein each R ₆ is independently selected from H and —CH ₃ . 32. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 31, wherein the two R ₆ groups attached to the same carbon are the same. 32. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-31, wherein each R ₆ is the same. 32. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 31, wherein each R ₆ is different. 35. The method of any one of claims 1 to 34,

giga

A compound selected from, or a pharmaceutically acceptable salt thereof. 35. The method of any one of claims 1 to 34,

giga

A compound selected from, or a pharmaceutically acceptable salt thereof. 37. The compound of any one of claims 1 to 36, wherein each R ₇ is independently selected from halogen, hydroxyl, C ₁ -C ₃ alkyl, and C ₁ -C ₃ haloalkyl. acceptable salts. 38. The compound of any one of claims 1-37, wherein each R ₇ is independently selected from halogen, hydroxyl, -CH ₃ , and -CF ₃ , or a pharmaceutically acceptable salt thereof. 39. The compound of any one of claims 1-38, wherein each R ₇ is independently selected from F, hydroxyl, -CH ₃ , and -CF ₃ , or a pharmaceutically acceptable salt thereof. 40. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 39, wherein each R ₇ is independently F. 38. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 37, wherein n is 0. 38. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 37, wherein n is 1. 43. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-42, wherein each R ₈ is hydrogen or two R ₈ groups are taken together to form oxo. 43. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 42, wherein each R ₈ is hydrogen. 43. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 42, wherein two R ₈ groups are taken together to form oxo. 46. The compound of any one of claims 1-45, wherein each R ₉ is independently selected from hydrogen, C ₁ -C ₃ alkyl, and —C(=O)—C ₁ -C ₃ alkyl; or A pharmaceutically acceptable salt thereof. 47. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 46, wherein each R ₉ is independently selected from hydrogen and C ₁ -C ₃ alkyl. 48. The compound of any one of claims 1-47, wherein each R ₉ is independently selected from hydrogen, —CH ₃ , —CH ₂ CH ₃ , and —CH(CH ₃ ) ₂ . acceptable salts. 37. The method of any one of claims 1 to 36,

giga

A compound selected from, or a pharmaceutically acceptable salt thereof. 50. The method of any one of claims 1-49, wherein L is a linker of 1 to 12 carbon atoms in length, wherein at least one carbon atom is C(=O), O, N(R ₉ ), S, C optionally replaced by ₂ -alkenyl, C ₂ -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl, wherein R ₉ , C ₂ -alkenyl, cycloalkyl, aryl, heterocycle and heteroaryl are each independently is substituted with 0, 1, 2 or 3 R _S , a compound or a pharmaceutically acceptable salt thereof. 51. The linker according to any one of claims 1 to 50, wherein L is a linker of 1 to 10 carbon atoms in length, wherein at least one carbon atom is C(=O), O, N(R ₉ ), S, C optionally replaced by ₂ -alkenyl, C ₂ -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl, wherein R ₉ , C ₂ -alkenyl, cycloalkyl, aryl, heterocycle and heteroaryl are each independently is substituted with 0, 1, 2 or 3 R _S , a compound or a pharmaceutically acceptable salt thereof. 52. The method of any one of claims 1-51, wherein L is a linker of 1 to 8 carbon atoms in length, wherein at least one carbon atom is C(=O), O, N(R ₉ ), S, C optionally replaced with ₂ -alkenyl, C ₂ -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl, wherein R ₉ , C ₂ -alkenyl, cycloalkyl, aryl, heterocycle and heteroaryl are each independently is substituted with 0, 1, 2 or 3 R _S , a compound or a pharmaceutically acceptable salt thereof. 53. The method of any one of claims 1-52, wherein L is a linker of 1 to 6 carbon atoms in length, wherein at least one carbon atom is C(=O), O, N(R ₉ ), S, C optionally replaced by ₂ -alkenyl, C ₂ -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl, wherein R ₉ , C ₂ -alkenyl, cycloalkyl, aryl, heterocycle and heteroaryl are each independently is substituted with 0, 1, 2 or 3 R _S , a compound or a pharmaceutically acceptable salt thereof. 54. The method of any one of claims 1-53, wherein one or more carbon atoms of linker L are optionally replaced by C(=O), O, N(R ₉ ), S, cycloalkyl, aryl, heterocycle or heteroaryl. and wherein R ₉ , C ₂ -alkenyl, cycloalkyl, aryl, heterocycle and heteroaryl are each independently substituted with 0, 1, 2 or 3 R _S , a compound or a pharmaceutically acceptable salt thereof. 55. The method of any one of claims 1-54, wherein one or more carbon atoms of linker L are optionally replaced by O, N(R ₉ ), cycloalkyl, or heterocycle, wherein R ₉ , cycloalkyl, and heterocycle are A compound or a pharmaceutically acceptable salt thereof, each independently substituted with 0, 1, 2 or 3 R _S . 56. The compound or pharmaceutically acceptable compound thereof according to any one of claims 1 to 55, wherein at least one carbon atom of linker L is replaced by a heterocycle substituted with 0, 1, 2 or 3 R _S . salt. 56. The compound or a pharmaceutically acceptable compound thereof according to any one of claims 1 to 55, wherein at least two carbon atoms of the linker L are replaced by a heterocycle substituted with 0, 1, 2 or 3 R _S . salt. 58. The compound or pharmaceutically acceptable salt thereof according to claim 56 or 57, wherein the heterocycle is selected from piperidine and piperazine, each substituted with 0, 1, 2 or 3 R _S . 58. The method of claim 56 or 57, wherein the heterocycle is

A compound selected from, or a pharmaceutically acceptable salt thereof. 50. The method of any one of claims 1-49, wherein the linker L is

A compound selected from, or a pharmaceutically acceptable salt thereof. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof, wherein each hydrogen atom is independently and optionally replaced with a deuterium atom. 62. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 61 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 63. The pharmaceutical composition of claim 62, wherein the compound or a pharmaceutically acceptable salt thereof is present in a therapeutically effective amount. A method of treating cancer in a subject in need thereof, the compound according to any one of claims 1 to 61, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 62 or 63. A method comprising administering to the subject. 65. The method of claim 64, wherein the cancer is prostate cancer, head and neck cancer, skin cancer, sarcoma, renal cell carcinoma, adrenocortical carcinoma, bladder cancer, lung cancer, gastric carcinoma, esophageal carcinoma, pancreatic adenocarcinoma, colorectal cancer, connective tissue cancer, glioblastoma multiforme, a method selected from cervical cancer, uterine cancer, ovarian cancer and breast cancer. 66. The method of claim 64 or 65, wherein the cancer is prostate cancer. 67. The method of any one of claims 64-66, wherein the cancer is androgen receptor positive. 68. The method of any one of claims 64-67, wherein the subject has previously been treated with an anticancer agent. 69. The method of claim 68, wherein the anticancer agent is enzalutamide, apalutamide, bicalutamide, darolutamide, flutamide, abiratarone, or a combination of any of these. 70. The method of claim 69, wherein the anticancer agent is enzalutamide. 62. Use of a compound according to any one of claims 1 to 61 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 62 or 63 for the treatment of cancer. 72. The method of claim 71, wherein the cancer is prostate cancer, head and neck cancer, skin cancer, sarcoma, renal cell carcinoma, adrenocortical carcinoma, bladder cancer, lung cancer, gastric carcinoma, esophageal carcinoma, pancreatic adenocarcinoma, colorectal cancer, connective tissue cancer, glioblastoma multiforme, Use selected from cervical cancer, uterine cancer, ovarian cancer and breast cancer. 73. The method of claim 71 or 72, wherein the cancer is prostate cancer. 74. The method of any one of claims 71-73, wherein the cancer is androgen receptor positive. 62. Use of a compound according to any one of claims 1 to 61 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 62 or 63 in the manufacture of a medicament. 76. The method of claim 75, wherein the medicament is prostate cancer, head and neck cancer, skin cancer, sarcoma, renal cell carcinoma, adrenocortical carcinoma, bladder cancer, lung cancer, gastric carcinoma, esophageal carcinoma, pancreatic adenocarcinoma, colorectal cancer, connective tissue cancer, glioblastoma multiforme, Use for treating a cancer selected from cervical cancer, uterine cancer, ovarian cancer and breast cancer. 77. The use according to claim 76, wherein the cancer is prostate cancer. 78. Use according to claim 76 or 77, wherein the cancer is androgen receptor positive. 64. A method of inhibiting cell growth, comprising contacting the cell with a compound according to any one of claims 1-61 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 62 or 63 . 80. The method of claim 79, wherein the cell is a cancer cell. 81. The method of claim 80, wherein the cancer cell is a prostate cancer cell. 82. The method of any one of claims 79-81, wherein the cell is androgen receptor positive. The compound of formula (1) according to claim 1, wherein the compound is a compound of formula (1A):

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